Original Article

Gene Therapy (2010) 17, 1152–1161; doi:10.1038/gt.2010.51; published online 15 April 2010

Randomized, double-blind, placebo-controlled clinical trial of hepatocyte growth factor plasmid for critical limb ischemia

H Shigematsu1, K Yasuda2, T Iwai3, T Sasajima4, S Ishimaru5, Y Ohashi6, T Yamaguchi7, T Ogihara8 and R Morishita9

  1. 1Department of Vascular Surgery, Tokyo Medical University, Tokyo, Japan
  2. 2Hokkaido Chuo Rosai Hospital Spinal Cord Injury Center, Japan Labour Health and Welfare Organization, Hokkaido, Japan
  3. 3Tsukuba Vascular Center and Buerger's Disease Research Institute (NPO), Moriya Keiyu Hospital, Ibaraki, Japan
  4. 4First Department of Surgery, Asahikawa Medical University, Hokkaido, Japan
  5. 5Center for Endovascular Therapy, Toda Chuo General Hospital, Saitama, Japan
  6. 6Department of Biostatistics, School of Public Health, University of Tokyo, Tokyo, Japan
  7. 7Department of Clinical Trial Data Management, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
  8. 8Osaka General Medical Center, Osaka, Japan
  9. 9Department of Clinical Gene Therapy, Osaka University Graduate School of Medicine, Osaka, Japan

Correspondence: Professor H Shigematsu, Department of Vascular Surgery, Tokyo Medical University, 6-7-1 Nishi-Shinjuku, Shinjuku-ku, Tokyo 160-0023, Japan. E-mail: hshige@tokyo-med.ac.jp

Received 30 November 2009; Revised 28 February 2010; Accepted 3 March 2010; Published online 15 April 2010.



Hepatocyte growth factor (HGF) is a potent angiogenic factor. The efficacy and safety of intramuscular injection of a naked plasmid encoding human HGF gene (beperminogene perplasmid, Collategene) was investigated in patients with critical limb ischemia (CLI) in a multicenter, randomized, double-blind, placebo-controlled trial. The randomization ratio for plasmid to placebo was 2:1. Injection sites were selected in each patient limb based on angiographic findings. Placebo or plasmid was injected on days 0 and 28. Evaluation of efficacy was carried out after 12 weeks. The primary end point was the improvement of rest pain in patients without ulcers (Rutherford 4) or the reduction of ulcer size in patients with ulcer(s) (Rutherford 5). Secondary end points were ankle-brachial pressure index, amputation, and quality of life (QOL). Forty-four patients were treated, and we performed interim analysis of efficacy in 40 patients. The overall improvement rate of the primary end point was 70.4% (19/27) in HGF group and 30.8% (4/13) in placebo group, showing a significant difference (P=0.014). In Rutherford 5 patients, HGF achieved a significantly higher improvement rate (100% [11/11]) than placebo (40% [2/5]; P=0.018). HGF plasmid also improved QOL. There were no major safety problems. HGF gene therapy is safe and effective for CLI.


angiogenesis; critical limb ischemia; hepatocyte growth factor; HGF



The clinical consequences of peripheral arterial disease (PAD) include pain on walking (claudication), pain at rest, and loss of part (or all) of the ischemic limb. Critical limb ischemia (CLI), the severest form of PAD, is estimated to develop in 500–1000 per million individuals worldwide annually.1 Surgical and endovascular revascularization is the treatment of first choice for CLI, and successful surgery can achieve dramatic improvement of symptoms. However, some patients are not candidates for revascularization and need medical therapy. Unfortunately, there is no effective medical therapy for CLI. With current therapy, it can be expected that >25% of CLI patients will require major limb amputation within 12 months,2 and the annual mortality rate exceeds 20%.3 Thus, many patients are forced to undergo amputation, and their quality of life (QOL) is profoundly impaired.

Therapeutic angiogenesis is a new strategy that attempts to improve the perfusion of ischemic vascular beds by promoting the formation of new blood vessels. Hepatocyte growth factor (HGF) is a potent angiogenic protein that activates the transcription factor ets-1 through the c-met receptor.4 In various animal models, transfection of naked plasmid DNA encoding the human HGF gene has achieved effective angiogenesis.5, 6, 7, 8, 9, 10, 11

The first human clinical trial of HGF gene therapy for PAD was performed in Japan, and showed that intramuscular injection of naked HGF plasmid was well tolerated.12 A subsequent multicenter, randomized, double-blind, dose-finding, placebo-controlled, trial performed in the USA showed that an injection of the HGF gene increased the tissue perfusion compared with placebo.13

The present trial in a multicenter, randomized, double-blind, placebo-controlled trial was performed with the following objectives: (1) to evaluate the efficacy of HGF gene therapy by using ‘reduction of ulcer size’ (for Fontaine IV) and ‘decrease in rest pain’ (for Fontaine III) as the primary end point in CLI patients who were not eligible for revascularization and (2) to assess the safety of this method.



A total of over 300 patients were pre-screened between February 2004 and June 2007. Among them, 121 patients met the pre-screening criteria and gave informed consent. During the 4-week screening period, 77 of these 121 patients were eliminated. The major reasons for exclusion were the presence of cancer (including suspected cancer), proliferative diabetic retinopathy, and other serious complications. Finally, 46 patients were randomized and 44 patients were treated in 30 of 57 centers. Two of the randomized patients were not treated because of the rapid progression of CLI and detection of proliferative retinopathy before administration in one case each (Figure 1). According to the study protocol, when the number of patients evaluated for efficacy reached 40, interim analysis was carried out. At that time, there were 27 patients in the HGF group and 13 in the placebo group. The efficacy analysis set included two patients who withdrew before assessment in week 12 because of worsening of CLI and severe adverse effects (both were in the placebo group). The safety analysis set consisted of 41 patients (HGF group: 28; placebo group: 13), including one patient who was excluded from efficacy analysis because of violation of the enrollment criteria (the patient did not have CLI).

Figure 1.
Figure 1 - Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact help@nature.com or the author

Flow chart of patient progression from randomization to analysis.

Full figure and legend (139K)

Average of ankle blood pressure during observation period showed <70mmHg in all patients. The mean age was 71.9±7.6 years in the HGF group and 72.8±7.3 years in the placebo group, and 51.9 and 61.5% of patients in the respective groups had diabetes mellitus (Fisher's exact test: P=0.74). Baseline characteristics were well balanced between the two groups, as shown in Table 1a and b. When early termination of the trial was decided on the basis of the results of the interim analysis, information about the allocation of treatment was opened to the investigators. As three patients (HGF group: 1; placebo group: 2) of the 44 treated had not been evaluated at the time when it was decided to terminate the trial, they were excluded from the analyses.

Primary end points

In week 12 of the study, the improvement rate of Fontaine III and IV (Rutherford 4 and 5) patients combined was 70.4% (19/27) in the HGF plasmid group versus 30.8% (4/13) in the placebo group. There was a significant difference of efficacy between HGF plasmid therapy and placebo therapy (P=0.014; Table 2) according to the Cochran–Mantel–Haenszel χ2 test. Among the patients with Rutherford 5/Fontaine IV disease (ischemic ulcers), HGF plasmid achieved a significantly higher improvement rate (100%, 11/11) compared with placebo therapy (40%, 2/5) (P=0.018 by Fisher's exact test). A decrease of ischemic ulcer size continued over time after HGF plasmid injection, as shown in Figure 2a. The mean ulcer size was reduced by approximately 70% in week 12 compared with earlier HGF plasmid therapy, whereas it did not decrease in the placebo group. Complete healing of ulcers was observed in 4 out of 11 patients (36.4%) from the HGF plasmid group, versus 1 out of 5 patients (20.0%) from the placebo group. In the Rutherford 4/Fontaine III patients, HGF plasmid therapy achieved a higher improvement rate (50%, 8/16) of rest pain compared with placebo therapy (25%, 2/8) (Fisher's exact test: P=0.39).

Figure 2.
Figure 2 - Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact help@nature.com or the author

Changes of efficacy end points (ulcer size, rest pain, and ABPI). ABPI, ankle-brachial pressure index. In all figures, the solid line indicates the HGF group and the dotted line indicates the placebo group. The mean and standard error are shown. The number of patients is also shown under each figure. (a) Change of ischemic ulcer size. The improvement threshold was ‘−25%.’ (b) Change of rest pain (including Rutherford 5/Fontaine IV). The improvement threshold was ‘−20mm.’ (c) Change of ABPI. The improvement threshold was ‘+0.1.’

Full figure and legend (181K)

Secondary end points

Quality of life

We used the SF-36 questionnaire to assess QOL. As shown in Table 3, bodily pain and mental health were significantly improved in the HGF plasmid group compared with the placebo group (t-test; bodily pain: P=0.036; mental health: P=0.023).

Rest pain (including Rutherford 5/Fontaine IV patients)

Thirty-six patients were evaluable (HGF group: 24; placebo group: 12) (Figure 2b) and there was no statistically significant difference between the two groups (P=0.71 by Student's t-test).

Ankle-brachial pressure index

Thirty-seven patients were evaluable (HGF group: 25; placebo group: 12). In the placebo group, mean ankle-brachial pressure index (ABPI) suddenly increased at 10 weeks after starting treatment (Figure 2c). At the end of the 12-week treatment period, no statistically significant difference was observed between the groups (P=0.94 by Student's t-test).

Limb salvage

During the 12-week period, no major amputations were performed in either group. Only one patient who received placebo went to minor amputation in Fontaine IV at 62 days after the first injection, whereas no patients went to amputation in HGF group during the treatment period. No significant difference was observed between the two groups (P=0.33 by Fisher's exact test).

Adverse events

Thirty-nine subjects (HGF plasmid group: 27; placebo group: 12) experienced at least one adverse event. Serious adverse events occurred in nine patients (six in the HGF plasmid group and three in the placebo group), as shown in Table 4. In one patient, prostate cancer was confirmed by biopsy and was reported as a serious adverse event. In this patient, biopsy was performed because a tumor marker (prostate-specific antigen-α1–antichymotripsin complex) increased after HGF plasmid administration. However, the tumor marker level returned to the range before administration without any treatment, so it was considered highly possible that this patient already had cancer before treatment. There was no difference between the two groups with respect to the progression of diabetic retinopathy. Although some patients had high serum levels of HGF protein after HGF plasmid administration, there was no significant difference between the two groups. No patient developed antibodies to HGF protein, E. coli protein, or DNA.



The results of follow-up for a maximum of 15 months are shown in Table 5. The mean ulcer size temporarily increased after 24 weeks because the ulcer of one patient was enlarged by injury at that time. Ischemic ulcers were healed in four of the nine patients who were assessed at 24 weeks. These results suggested that the efficacy of HGF plasmid therapy is maintained for a relatively long period.


The number of patients available for safety assessment was 29, which consisted of patients exposed to the active drug during the treatment phase. No characteristic adverse events were observed throughout the follow-up period. Three serious adverse events occurred in one patient between the 12- and 24-week assessments, five serious events occurred in four patients between the 24-week and 9-month assessments, and nine serious events occurred in six patients between 9 and 15 months. However, a causal relationship with the study drug could be ruled out for all these events. There was one death from acute myocardial infarction. There were no injection site abnormalities, no de novo malignancies, and no worsening of diabetic retinopathy during the follow-up period.



Recent progress in molecular biology has led to studies on therapeutic angiogenesis as a potential treatment option for ischemic diseases. Gene therapy has been explored using various angiogenic growth factors,14, 15, 16, 17, 18, 19, 20, 21, 22 and some of the results have suggested the usefulness of this therapy. This study is the first double-blind, randomized, placebo-controlled, multicenter clinical trial to show both improvement of symptoms (especially for ulcers) and improvement of QOL such as bodily pain and mental health by therapeutic angiogenesis in patients with CLI.

In this trial, any other treatment except bone marrow cell transplantation is allowed for concomitant use. Patients in whom the symptom had not improved by use of anti-platelet and/or prostaglandins during 1-month observation period were enrolled. In addition, patients who are not eligible for revascularization were selected. Considering that significant difference compared with placebo was shown under such condition, it can be said that HGF plasmid has potent effects compared with existing pharmacotherapy.

The most intriguing findings were obtained in our patients with ischemic ulcers (Rutherford 5/Fontaine IV). In these subjects, HGF plasmid therapy achieved 100% improvement after 12 weeks, whereas placebo therapy only achieved 40% improvement. The number of patients available for evaluation after follow-up was small, but the response to therapy noted at 12 weeks was maintained in most patients at 24 weeks, apart from one with progression of the primary disease and one with exacerbation of a leg ulcer by trauma. Only one patient who received placebo went to minor amputation in Fontaine IV at 62 days after initial injection, whereas no patients went to amputation in HGF group during treatment period. Until 15 months, two patients who received HGF plasmid went to amputation (patients who did not receive HGF plasmid were exempted from follow-up). As the rate of amputation in Japan is not so high, further studies to evaluate the efficacy of HGF gene therapy to avoid major amputation are necessary.

In contrast to the significant improvement of ischemic ulcers, changes of rest pain did not show a significant difference between the two groups. However, ‘bodily pain’ (a subscale of SF-36 that is an index of pain) improved significantly after treatment with HGF plasmid. This discrepancy supposedly is caused by the sample size and subjectivity of the pain evaluation. The change of ABPI was not associated with the ulcer healing, suggesting that HGF plasmid may act at the microvascular level.

During the clinical trial performed in the USA, the dosage used in this study (4.0mg of HGF plasmid on days 0 and 28) did not show efficacy.13 A possible reason for the difference in results may be related to the administration method. In the US trial, administration sites were predefined (four sites above the knee and four below the knee), whereas we selected the sites according to the locations of stenosis and obstruction in each patient.

Assessment of safety showed that approximately 200 adverse reactions were reported during 12 weeks of observation. Although some of these reactions, such as pain at the injection sites, were considered to be related to gene therapy, most of the reactions were unrelated. Adverse reactions that might be expected based on the mechanism of action of HGF, such as hemangioma or worsening of diabetic retinopathy, were not seen during the 12-week observation period or during subsequent follow-up for as long as 15 months. As the patients who received placebo were not followed, the comparable information is not available. Nine patients who received placebo entered into open label study with HGF plasmid. These patients did not show any safety concerns until 15 months. Another clinical trial of gene therapy using naked plasmid DNA has also shown the safety of this method.22 Of course, these findings do not establish the long-term safety of HGF plasmid. But at least there was no increase in the mean serum level of HGF protein, so HGF plasmid is unlikely to influence the whole body excluding the injection site. No serious abnormalities around the injection site were recognized in this trial. It is also noteworthy that there were only a few cases of peripheral edema. This outcome stands in marked contrast to reports on clinical trials of vascular endothelial growth factor (VEGF), in which 60% of the patients developed edema.23 Such a difference between HGF and VEGF might be due to a differing influence on vascular smooth muscle cell migration.24 As only a small number of patients have been evaluated for safety so far, it will be necessary to investigate the safety of HGF plasmid therapy further and obtain more data before making a final judgment.

In conclusion, the present multicenter, double-blind, placebo-controlled, randomized trial showed that intramuscular injection of HGF plasmid was well tolerated and can improve the symptoms (especially for ischemic ulcer) and QOL such as bodily pain and mental health of patients with CLI. However, further studies to evaluate the efficacy of HGF gene therapy on the improvement of rest pain, complete ulcer healing, amputation, cardiovascular death, and so on would be necessary.


Materials and methods

This trial was designed by AnGes MG, Inc. (Osaka, Japan) in collaboration with specialists in the field of PAD, gene therapy, and biostatistics. All authors of the manuscript were members of the scientific advisory board for this clinical trial. Formal data analysis was performed by a contract research organization (EPS Co., Ltd, Tokyo, Japan). The results of interim analysis were reviewed by an independent academic statistician (a member of the independent data monitoring committee).

Study design

This was a multicenter, randomized, double-blind, placebo-controlled trial conducted at 57 centers in Japan. The protocol was approved by the institutional review board at each study site, and this trial was conducted in accordance with the Good Clinical Practice Guidelines. The objectives, study design, and risks and benefits of participation were explained to all of the patients, and their written informed consent was obtained before enrollment.

A flowchart of the study is shown in Figure 3. Before administration, all patients were screened by an eligibility committee composed of vascular surgeons. All patients also received standard medication for CLI (for example anti-platelet agents), which was not changed throughout the study period. After evaluation of efficacy was completed (8 weeks after administration of the second dose of HGF plasmid or placebo), the study treatment code was opened for each patient. Those who had been treated with placebo could then receive HGF plasmid, if they wished.

Figure 3.
Figure 3 - Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact help@nature.com or the author

Study design. If the study drug was placebo, the subject could choose to enter stage 2 and receive the active drug.

Full figure and legend (91K)


Eligible patients were aged 40–84 years with chronic CLI and rest pain or non-healing ischemic ulcers (Rutherford 4/Fontaine III or Rutherford 5/Fontaine IV) persisting for a minimum of 4 weeks. The resting ABPI measured by Doppler ultrasound was <0.6 and the mean ankle blood pressure was <70mmHg in the affected limb according to three consecutive measurements performed in weeks −4, −2, and 0. When ankle blood pressure was not measurable (because of arterial calcification or local ulceration), the toe-brachial pressure index and toe pressure were measured instead (the cutoff value for toe-brachial pressure index was <0.5 and for toe pressure was <50mmHg). All subjects were ineligible for standard surgical or percutaneous revascularization and had shown no response to conventional drug therapy for at least 4 weeks. Patients with deep ulcers that exposed bone or tendon were excluded, as were those with clinical evidence of invasive infection (for example cellulitis or osteomyelitis) uncontrolled by antibiotics. Patients with serious cardiac, hepatic, renal, or hematological disease were also excluded. Furthermore, patients were excluded if they had any of the following: current evidence or a history of malignancy; proliferative diabetic retinopathy; neovascular age-related macular degeneration; sympathectomy or sympathetic block within 6 months; and revascularization or major amputation within 3 months.

Randomization and treatment

Patients were treated with either HGF plasmid or placebo. The randomization ratio for HGF plasmid to placebo therapy was 2:1 and patients were randomly allocated by the central registration center (Bellsystem24, Inc., Tokyo, Japan) using a modified minimization method. To balance baseline characteristics between the two groups, the Rutherford/Fontaine classification, gender, study site, and admission status (outpatient or inpatient) were used as factors for adjustment. At each institution, the study medication was administered in a blinded manner according to the instructions of the registration center.

This HGF plasmid consists of the cDNA fragment of human HGF (Eco RI/Not I, 2.2kbp) inserted into the pVAX1 vector (3.0kb) produced by Invitrogen Corporation (Carlsbad, CA, USA), which complies with the Food and Drug Administration document ‘Points to Consider on Plasmid DNA Vaccines for Preventative Infectious Disease Indications.’ To minimize the possibility of chromosomal integration, insertional mutagenesis through the activation of oncogenes, or inactivation of tumor suppressor genes, all sequences with possible homology to the human genome have been removed from the pVAX1 DNA, along with any sequences that are not necessary for replication in E. coli or for expression of a recombinant protein in mammalian cells.

After the 4-week observation period, 0.5mg of HGF plasmid (or placebo) was diluted in 3ml of sterile saline, and eight injections (a total dose of 4mg per 24ml) were directly injected into the calf muscles and/or distal thigh muscles of the ischemic limbs under ultrasound guidance. After 4 weeks, a second course was administered similarly, so the total dose of HGF plasmid was 8mg per patient in the treated group.

End points

The Guideline for PAD recommends ‘relief of rest pain,’ ‘healing of ulcers,’ ‘amputation,’ and ‘incidence of complications and total mortality rate’ as primary end points for clinical studies of CLI.25. It is ethically impossible to use ‘amputation’ and ‘mortality rate’ as the primary end points for a placebo-controlled study of a severe disease such as CLI in Japan at the time we started the study. Therefore, rest pain and ischemic ulcer size were selected as the primary end points for this study.

The primary end point was the improvement rate determined in week 12 of the study. For Rutherford 4/Fontaine III patients, the improvement rate was determined from the change of rest pain assessed on a 100-mm VAS. For the Rutherford 5/Fontaine IV patients, the improvement rate was determined from the change of ischemic ulcer size. Improvement of rest pain was defined as a reduction of VAS scale length by >20mm compared with that in week 0 (baseline). If a patient required >1.3 times the baseline dose of medication for pain relief or started a new pain medication, rest pain was evaluated as ‘not improved’ irrespective of the change of the VAS. For ischemic ulcers, a reduction in the size (square root of the long axis multiplied by the short axis) of the designated largest ischemic ulcer by >25% (approximately a 50% change of area) was defined as improvement. The selection of the ischemic ulcer to be measured was decided by the central reading system by four vascular surgeons. At the observation period, the basic information and the typical pictures of ischemic ulcer were provided to the committee. The committee decided which ulcers could be evaluated. Then, the measurement of the ulcer size was performed by the sites using the same scales. As the secondary end points, QOL (assessed with the SF-36 questionnaire), ABPI, and limb salvage were examined.

In this trial, the evaluation of the primary end point was performed at 12 weeks after the first injection. After the evaluation of primary end point, the database was locked and the study treatment code was opened for each patient. The patients who received the placebo were consulted whether they wish to receive injection of HGF plasmid. The patients who agreed to receive injection of HGF plasmid were enrolled in an open label study. In these patients, the primary end point was evaluated at 12 weeks after the first injection of HGF plasmid, similar to the original trial. Follow-up was also similar to the original trial. The patients who did not agree to receive HGF plasmid were not further followed.


Safety was assessed by evaluation of adverse events, concomitant medications, ECG findings, laboratory data (blood chemistry, hematology tests, and urinalysis), vital signs, physical findings, the results of screening for cancer and retinopathy, and assays for HGF protein, HGF antibodies, E. coli protein antibodies, and DNA antibodies. For the patients to whom HGF plasmid was administered, follow-up examination was carried out at 6, 9, and 15 months.

Statistical analysis

Assuming an improvement rate (combined Rutherford/Fontaine category) of 62% in the HGF plasmid group and 30% in the placebo group, it was calculated that 49 patients per group were required to conduct statistical analysis with a significance of P<0.05 (two-tailed) and a power of test of 90%, if the ratio of patients in the two groups was set at 1:1. However, this ratio was set at 2:1 because we wanted a larger safety analysis set for HGF plasmid therapy. Accordingly, the required number of patients was calculated to be 74 and 37 in HGF plasmid and placebo groups, respectively. The target number of patients was, therefore, set at 80 for the HGF plasmid group and 40 for the placebo group. After the trial was started, it was found that many patients did not satisfy the entry criteria and recruitment was slow due to the limited availability of patients with CLI and the high rate of screening failure. Accordingly, we decided to perform an interim analysis after 40 patients were available with 12 weeks of follow-up data, and we amended the protocol. Rules for stopping the trial based on the results of interim analysis were defined in the study protocol as follows:

  1. A demonstrated statistically significant advantage of HGF plasmid therapy over placebo therapy (P<0.02).
  2. Very little chance of no statistical difference emerging on final analysis (<10% by Bayesian prediction using the non-informative prior).26
  3. Unacceptable adverse drug reactions in the HGF plasmid group.

Comparison of the primary end point was performed with the Cochran–Mantel–Haenszel χ2 test after subjects were stratified by the Rutherford/Fontaine classification. Changes of SF-36 domain scores were compared by the t-test without adjustment for multiplicity.


Conflict of interest

All authors attended 1-day meetings sponsored by Anges MG, Inc. several times, and they received an honorarium for participation. The eligibility judgment committee (Drs Shigematsu, Iwai, Sasajima, and Ishimaru) received remuneration for their contribution. Drs Ogihara and Morishita own stock in AnGes MG, Inc. and Dr Morishita is a founder and board member of the company. Although they were involved in designing the trial and writing the report after the treatment codes were opened, they did not take part in the conduct of this trial. Specifically, they were not involved in enrollment, allocation, or evaluation of patients. The other authors do not have any interest in AnGes MG, Inc.



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We thank Data and Safety Monitoring Board (DSMB), which consisted of Kensuke Esato (Yamaguchi Prefectural University), Kenichiro Okadome (Saiseikai Fukuoka General Hospital), Tohru Ohe (The Sakakibara Heart Institute of Okayama), Masayasu Matsumoto (Hiroshima University Hospital), and Yasuo Saijo (Hirosaki University Hospital) as the core members. Shiro Takahara (Osaka University Hospital) and Noriaki Tanaka (Okayama University Hospital) were special invited members of the DSMB. We also thank Independent Data Monitoring Committee (IDMC) consisting of Fumimaro Takaku (Jichi Medical University), Seiichiro Yamamoto (National Cancer Center), and the core members of the DSMB. This trial was funded by AnGes MG, Inc. (Osaka, Japan).



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Keeping in touch with angiogenesis

Nature Medicine News and Views (01 Apr 2000)