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EMR200147-500: A prospective, randomized, placebo-controlled, double-blind clinical trial to evaluate whether EGRIFTA (tesamorelin for injection), 2 mg once daily SC, increases the risk of development or progression of diabetic retinopathy when administered to HIV-infected subjects with abdominal lipohypertrophy and concomitant diabetes

Description

Human immunodeficiency virus (HIV, the virus that causes AIDS)-associated lipodystrophy is a medical condition characterized by body changes, including accumulation of fat in the stomach cavity, breasts, and the upper back associated with multiple blood and hormone disturbances. EGRIFTA is a drug that mimics human hypothalamic GHRF (hGHRF, a hormone in the body made by a gland near the brain that increases other hormones such as Growth Hormone) which was shown to significantly reduce visceral adipose tissue (VAT, which is a name for fat in stomach cavity) after 26 weeks of treatment compared with injections of placebo (a substance with no activity) in two relatively large multi-center, yearlong studies. After 26 weeks, there was no change in blood sugar between the treated and the placebo groups. The mean change in hemoglobin A1c (HbA1c, a measure of what the blood sugar has been over the prior 3 months time) from baseline to 26 weeks was slightly higher in the treated group compared to the placebo group, but this is unlikely to represent a medically important difference. After 52 weeks the change in HbA1C from baseline was no longer considered different between groups.The subject populations examined in these studies may not be reflective of the diabetic HIV-infected subjects with increased abdominal fat who will be treated with EGRIFTA in the present study. EGRIFTA was approved by the US FDA on November 10, 2010 and is indicated for the reduction of excess abdominal fat in HIV-infected patients with lipodystrophy. As a condition of approval of EGRIFTA, a study will be conducted to assess the potential of EGRIFTA to cause or worsen diabetic retinopathy (DR, blood vessel problems in the eye that can lead to blindness in some cases) in HIV-infected subjects who also have abdominal lipohypertrophy and diabetes.Design: This is a placebo-controlled (meaning some participants will have injections of an inactive substance instead of EGRIFTA, double-blind (meaning neither the study team nor the participant) clinical trial to evaluate whether EGRIFTA (tesamorelin for injection), 2 mg once daily, increases the risk of development or progression of DR when given to HIV-infected subjects with abdominal lipohypertrophy and diabetes.The primary objective of the trial is to evaluate whether EGRIFTA, 2 mg once daily, is not worse than placebo for a minimum of 36 months of treatment as assessed by a worsening of DR.Following assignment to a treatment group, subjects will return to the study site for laboratory and safety assessments at 1.5, 3, 6, 12, 18, 24, 30, and 36 months. Additional visits will occur at Months 9, 15, 21, 27, and 33 for assessment of side effects and other medications and resupply of study drug. Assessment of DR will occur at screening and at the Months 6, 12, 24, and 36 visits. Main entry criteria: Adult HIV-infected subjects with abdominal lipohypertrophy and type 2 diabetes. Stable anti-retroviral therapy (ART, the medications used to treat HIV) at least 8 weeks; current HbA1c between 6.0% and 12.0%; Diabetes has been treated for at least 1 year by diet alone, insulin alone, pills, or other injections plus insulin according to current American Diabetes Association (ADA) guidelines, and doses have been stable for 3 months; cholesterol lowering drugs allowed if stable dose for at least 2 months; ; Women: not pregnant or breast feeding, are post-menopausal, surgically unable to have babies, or using acceptable birth control; Women over 40 years old: normal mammogram within 6 months prior; Men: normal prostate exam and PSA (prostate specific antigen, a blood test which is increased with prostate cancer and other conditions) within 6 months.Exclusion: Type 1 diabetes; Body mass index (BMI) < 20 kg/m2; Opportunistic infection or AIDS-defining illness within 3 months; Current or past malignancy (except certain skin and cervical cancers); Women: personal or family history (mother or sister) of breast cancer; severe DR; Current or past eye infection that would prevent assessment of DR; Previous DR treatment; certain hormonal problems; Head xrays or head trauma affecting hormones; Uncontrolled high blood pressure, severe heart disease, stroke; Abnormal liver or kidney function; severe anemia Men: change in, or high dose of, testosterone within 2 months; Anabolic steroids, certain hormonal treatments, drug or alcohol dependence within 6 months; drug treatment for overweight within 3 months.Primary endpoint: The difference in percentages of subjects with a significant increase in DR scale between subjects treated with EGRIFTA and those treated with placebo.Statistical methods: With a 2.5% 1-sided type I error rate (the chance that the study will come to the wrong conclusion), 80% power (how likely the study will show a positive result), and a 2:1 randomization ratio (2 participants on EGRIFTA for each on placebo), a total of 453 subjects (302 EGRIFTA and 151 placebo) will be required to show that the DR progression rate for the EGRIFTA-treated subjects is greater than that of the placebo subjects by no more than 10%. Assuming a 30% dropout rate, a total of 648 subjects (432 EGRIFTA and 216 placebo) will be needed for this trial.

Phase

N/A

Inclusion and Exclusion Criteria

  • Subject has given written informed consent and is willing to comply with the requirements of the protocol;
  • Subject is an adult man or woman (≥ 18 years old);
  • Subject has laboratory confirmed HIV infection;
  • Subject is receiving ART that has been stable for at least 8 weeks prior to screening;
  • Subject has physical evidence of abdominal lipohypertrophy, as determined by the examining study physician;
  • Subject has T2DM as determined by previous HbA1c ≥ 6.5%, previous fasting plasma glucose - ≥ 126 mg/dL (7.0 mmol/L), and/or previous 2-hour plasma glucose ≥ 200 mg/dL (11.1 mmol/L) during oral glucose tolerance testing (OGTT), and/or previous random plasma glucose ≥ 200 mg/dL (11.1 mmol/L) with symptoms of uncontrolled DM; - if subject has been diagnosed with T2DM and is on glucose lowering medications for greater than 1 year the above glucose parameters do not apply;
  • Subject, at the time of screening, has HbA1c between 6.0% and 12.0%;
  • Subject's diabetes has been treated for at least 1 year by diet alone, individuals who are on a stable dose (at least 3 months) of insulin, an OHA, or a GLP-1 analogue plus insulin to control diabetes are permitted if their HbA1C is below 6.0%. OHA, GLP-1 analogue, or OHA/GLP-1 analogue plus insulin according to current American Diabetes Association (ADA) guidelines, and doses have been stable for at least 3 months;
  • If the subject is using lipid lowering drugs, the dose must be stable for at least 2 months prior to screening;
  • Subject must have an electrocardiogram (ECG) without clinically significant abnormalities within 6 months prior to screening;
  • Pre-menopausal women of childbearing potential are eligible only if they are not pregnant (negative urine pregnancy tests at screening and baseline) or lactating and are using an acceptable form of birth control prior to study entry and for at least 2 months after completing treatment. Acceptable contraception is defined as two barrier methods, or one barrier method with a spermicide, or an intrauterine device, or an oral contraceptive;
  • Women of non-childbearing potential must be post-menopausal (no menses for more than 1 year) or surgically sterile (tubal ligation or hysterectomy);
  • Women over 40 years old must have a negative mammogram within 6 months prior to screening or a mammogram will be taken at screening;
  • Men must have a normal prostate exam and a prostate specific antigen (PSA) Individuals who are on a stable dose (at least 3 months) of insulin, less than or equal to 5 ng/mL within 6 months prior to screening or PSA and, for men 50 years of age or older, a prostate specific antigen will be measured at screening

  • Subject has Type 1 DM;
  • Subject has body mass index (BMI) < 18.5 kg.m2;
  • Subject has or has had an opportunistic infection or acquired immune deficiency syndrome (AIDS)-defining illness within 3 months of screening;
  • Subject has or has had a malignancy or, for women, personal or family (first degree relative) history of breast cancer. Exceptions are basal cell carcinoma, in situ carcinoma of the cervix, in situ anal carcinoma, treated and stable cutaneous squamous cell carcinoma. and stable Kaposi's sarcoma;
  • Pre-existing PDR or severe non-PDR (NPDR), defined as an ETDRS level of ≥ 53 in either eye;
  • Subject has or has had cytomegalovirus (CMV) retinitis, toxoplasmosis, or any other ocular infection that would prevent evaluation of DR;
  • Subject has previously been treated for DR (treatments such as laser photocoagulation, intravitreal injection, or vitrectomy);
  • Subject has any of the following illnesses or conditions:
  • hypopituitarism, history of pituitary tumor or pituitary surgery;
  • untreated hypothyroidism;
  • head irradiation or head trauma that has affected the somatotropic axis;
  • uncontrolled hypertension, defined as systolic pressure > 140 mm Hg and diastolic pressure > 90 mm Hg;
  • unstable CV condition, defined as: i. acute MI; ii. unstable angina; iii. decompensated congestive heart failure (CHF, new onset or exacerbation); iv. stroke; v. history of any of the above within 6 months prior to screening; f. hepatic abnormality, defined as aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 3 times the upper limit of normal (3 x ULN); g. renal abnormality, defined as serum creatinine > 2 x ULN; h. lipid metabolism abnormality, defined as fasting triglycerides > 1500 mg/dL; i. anemia, defined as hemoglobin ≤ 7 g/dL;
  • Drug or hormone use as follows
  • Men: change in regimen or supraphysiological dose of testosterone within 2 months prior to screening;
  • anabolic steroids, GH, GH secretagogue, GHRF products or analogs (including EGRIFTA

Sites

  • California

    • 5P21 Rand Schrader Clinic, Los Angeles, California, 90033
    • AIDS Research Alliance, Los Angeles, California, 90015
    • University of California CARE Clinic, Los Angeles, Los Angeles, California, 90035
    • Anthony Mills MD, Inc., Los Angeles, California, 90069
    • Pacific Coast Medical Group, Fountain Valley, California, 92708
    • Michael Keith Wensley, MD Inc - A Medical Corporation, Costa Mesa, California, 92626
    • Palmtree Clinical Research, Inc., Palm Springs, California, 92262
    • UCSD Antiviral Research Center, San Diego, California, 92103
    • VAMC, Infectious Disease Section 111W, San Francisco, California, 94121
  • Arizona

    • Spectrum Medical Group, Phoenix, Arizona, 85012
    • Southwest Center for HIV/AIDS, Phoenix, Arizona, 85004
  • Oregon

    • Fanno Creek Clinic, LLC, Portland, Oregon, 97219
  • Washington

    • Virginia Mason Medical Center, Seattle, Washington, 98112
  • Oklahoma

    • Harold Hamm Diabetes Center at University of Oklahoma, Oklahoma City, Oklahoma, 73104
  • Texas

    • Central Texas Clinical Research, Austin, Texas, 78705
    • UT Southwestern Medical Center, Atten: HIV Research Unit, Dallas, Texas, 75235
    • Dallas VA Medical Center, Dallas, Texas, 75216
    • St. Hope Foundation, Inc., Bellaire, Texas, 77401
    • Research Access Network, Houston, Texas, 77098
  • Missouri

    • Southampton Healthcare, Inc., St. Louis, Missouri, 63139
    • Southampton Clinical Research, Inc d.b.a. Central West Clinical Research, St. Louis, Missouri, 63108
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