Unacylated Ghrelin for Peripheral Arterial Disease

(GIFTII Trial)

Recruiting at 1 trial location

Overseen By Mary McDermott, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Northwestern University

Must not be taking: Study drugs

Disqualifiers: Amputation, Critical limb ischemia, Dialysis, others

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

Duration: 16 weeks

25 Participants Needed

Trial Summary

Do I need to stop taking my current medications to join the trial?

The trial protocol does not specify if you need to stop taking your current medications. However, if you are currently taking the study drug or have taken it in the past six months, you cannot participate.

What data supports the idea that Unacylated Ghrelin for Peripheral Arterial Disease is an effective treatment?

The available research shows that unacylated ghrelin may help reduce tissue damage in peripheral arterial disease by promoting muscle regeneration and reducing oxidative stress. In a study with diabetic mice, treatment with ghrelin improved blood flow and muscle structure, suggesting it could be a promising therapy for patients with this condition, especially those with diabetes. ^{1 2 3 4 5}

What safety data is available for Unacylated Ghrelin treatment?

The provided research does not directly address the safety data for Unacylated Ghrelin (UAG) in the context of Peripheral Arterial Disease. However, it mentions studies on UAG in other conditions, such as obesity and diabetes, suggesting its potential as a treatment for metabolic disorders. The safety, tolerability, and pharmacokinetics of a ghrelin receptor inverse agonist were evaluated in healthy subjects, but this is not specific to UAG. More targeted studies would be needed to assess the safety of UAG specifically for Peripheral Arterial Disease. ^{3 4 6 7 8}

Is the drug Unacylated Ghrelin a promising treatment for Peripheral Arterial Disease?

Yes, Unacylated Ghrelin shows promise as a treatment for Peripheral Arterial Disease. It has potential antioxidant effects that may reduce tissue damage, and it can improve blood flow and muscle repair, especially in diabetic patients. ^{1 2 3 7 8}

What is the purpose of this trial?

GIFT is a pilot, randomized, double-blinded clinical trial that will examine the effects of unacylated ghrelin on walking ability in people with peripheral artery disease (PAD) compared to placebo. Preliminary evidence suggests that unacylated ghrelin may improve blood flow to the extremities and promote improved skeletal muscle growth and energy use. A total of 30 participants with PAD will be randomized to one of two groups: unacylated ghrelin injections or placebo injections . Participants will self-administer the study drug or placebo subcutaneously once daily for four months. The primary outcome is change in six-minute walk distance between baseline and 4-month follow-up

Research Team

Mary McDermott, MD

Principal Investigator

Northwestern University

Eligibility Criteria

This trial is for individuals aged 55 or older with peripheral artery disease (PAD), evidenced by specific diagnostic criteria. They must be able to self-administer injections and not have major liver or kidney issues, recent surgeries, or other severe health conditions that limit walking ability. Pregnant women and those unable to store the medication properly are excluded.

Inclusion Criteria

I am 55 years old or older.

I have been diagnosed with peripheral artery disease.

Exclusion Criteria

I have severe blockage in my leg arteries causing pain and ulcers.

I use a wheelchair, cane, or walker to move around.

In addition to the above criteria, investigator discretion will be used to determine if the trial is unsafe or not a good fit for the potential participant

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive daily subcutaneous injections of unacylated ghrelin or placebo for four months

16 weeks

Participants self-administer daily

Follow-up

Participants are monitored for changes in walking ability and muscle function

4 weeks

Treatment Details

Interventions

• Placebo
• Unacylated Ghrelin

Trial Overview The GIFT trial is testing whether unacylated ghrelin injections can improve walking ability in PAD patients compared to a placebo. Participants will randomly receive either the real drug or a placebo daily for four months, with their walking distance measured before and after treatment.

Participant Groups

Group I: Unacylated ghrelin Active Control 1 Intervention

Participants randomized to unacylated ghrelin will self-administer 20 ug/kg unacylated ghrelin daily. Study drug is dispensed in syringes labeled with the participant's name, date of birth, expiration date, and instructions for administration. Syringes will NOT be labeled with the group assignment, ensuring that both the research team collecting data and study participants are blinded to group assignment (i.e. double blinded status). Study drug is stored and handled according to the University of Chicago Research Pharmacy Standard Operating Procedure (SOP).

Group II: Placebo Placebo Group 1 Intervention

Participants randomized to placebo will self-administer an identical-appearing solution of bacteriostatic saline daily.

Who Is Running the Clinical Trial?

Northwestern University

Lead Sponsor

Trials

1,674

Recruited

989,000+

National Institute on Aging (NIA)

Collaborator

Trials

1,841

Recruited

28,150,000+

Findings from Research

Unacylated-ghrelin (UnAG) promotes skeletal muscle regeneration in a mouse model of peripheral artery disease by activating p38/MAPK signaling and increasing the expression of the antioxidant enzyme superoxide dismutase-2 (SOD-2), which protects against oxidative stress-induced damage.

The regeneration process is linked to the up-regulation of miR-221/222, which is negatively correlated with p57(Kip2) expression, suggesting that UnAG could be a promising therapeutic option for treating muscle damage caused by oxidative stress.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Unacylated ghrelin promotes skeletal muscle regeneration following hindlimb ischemia via SOD-2-mediated miR-221/222 expression. Togliatto, G., Trombetta, A., Dentelli, P., et al.[2021]

Diabetic patients and db/db mice with type 2 diabetes have significantly lower levels of the hormone ghrelin, which is linked to impaired vascular repair and increased risk of peripheral artery disease (PAD).

Treatment with exogenous ghrelin in diabetic mice improved blood flow and promoted vascular repair after limb ischemia, suggesting that ghrelin could be a promising new therapy for enhancing circulation in diabetic patients with PAD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dysregulation of ghrelin in diabetes impairs the vascular reparative response to hindlimb ischemia in a mouse model; clinical relevance to peripheral artery disease. Neale, JPH., Pearson, JT., Thomas, KN., et al.[2021]

In a study of 552 young men undergoing a 6-month exercise program, increases in unacylated ghrelin (UAG) levels were linked to significant reductions in weight, fat mass, and waist circumference, indicating its potential role in weight management.

The relationship between UAG levels and reductions in waist circumference was notably stronger than its association with overall fat percentage, suggesting that UAG may be particularly important in addressing central obesity during exercise interventions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Unacylated ghrelin is associated with changes in body composition and body fat distribution during long-term exercise intervention. Cederberg, H., Rajala, U., Koivisto, VM., et al.[2016]

PF-05190457, an oral ghrelin receptor inverse agonist, was found to be well-tolerated in healthy adults, with rapid absorption and a half-life suitable for daily dosing, indicating its potential for safe use in treating conditions like insomnia.

The drug effectively blocked ghrelin-induced growth hormone release by 77% at a 100 mg dose and delayed gastric emptying, but some side effects like increased heart rate and somnolence were noted, which diminished with continued use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetics and pharmacodynamics of PF-05190457: The first oral ghrelin receptor inverse agonist to be profiled in healthy subjects. Denney, WS., Sonnenberg, GE., Carvajal-Gonzalez, S., et al.[2021]

Patients with idiopathic pulmonary arterial hypertension (IPAH) had significantly higher levels of plasma ghrelin compared to control subjects, suggesting a potential role of ghrelin in the disease.

Elevated ghrelin levels in IPAH patients correlated positively with important clinical markers such as N-terminal brain natriuretic peptide (N-BNP), pulmonary arterial systolic pressure (PASP), and right ventricle diameter (RVD), indicating that ghrelin could serve as a novel prognostic biomarker and a potential therapeutic target.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ghrelin and its relation with N-terminal brain natriuretic peptide, endothelin-1 and nitric oxide in patients with idiopathic pulmonary hypertension. Yang, D., Liu, Z., Yang, Z.[2015]

In a study involving 20 underweight patients with chronic obstructive pulmonary disease (COPD), ghrelin administration significantly improved exercise capacity, as indicated by a 1.2 mL/kg/min increase in peak oxygen uptake compared to placebo.

Ghrelin treatment also led to beneficial changes in several cardio-respiratory functions, including reduced ventilatory equivalents for oxygen and carbon dioxide, and improved O2-pulse, suggesting it enhances both respiratory and cardiac efficiency during exercise.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of ghrelin treatment on exercise capacity in underweight COPD patients: a substudy of a multicenter, randomized, double-blind, placebo-controlled trial of ghrelin treatment. Miki, K., Maekura, R., Nagaya, N., et al.[2021]

In a study involving 8 morbidly obese non-diabetic subjects, the co-administration of acylated ghrelin (AG) and unacylated ghrelin (UAG) significantly reduced insulin levels shortly after treatment, suggesting improved insulin sensitivity.

In contrast, UAG alone did not affect insulin, glucose, free fatty acids, or growth hormone levels, indicating that the combination of AG and UAG may be necessary for metabolic benefits in this population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of acute administration of acylated and unacylated ghrelin on glucose and insulin concentrations in morbidly obese subjects without overt diabetes. Kiewiet, RM., van Aken, MO., van der Weerd, K., et al.[2016]

Unacylated ghrelin (UAG) is emerging as an important hormone with its own receptor and the ability to inhibit the effects of acylated ghrelin (AG), suggesting it plays a significant role in metabolic regulation.

UAG has been shown to effectively lower ghrelin levels in obese diabetic individuals and improve blood sugar levels after meals, indicating its potential as a therapeutic target for metabolic disorders like diabetes and obesity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Des-acyl ghrelin: a metabolically active peptide. Delhanty, PJ., Neggers, SJ., van der Lely, AJ.[2021]

References

1. England pubmed.ncbi.nlm.nih.gov

Unacylated ghrelin promotes skeletal muscle regeneration following hindlimb ischemia via SOD-2-mediated miR-221/222 expression. [2021]

2. England pubmed.ncbi.nlm.nih.gov

Dysregulation of ghrelin in diabetes impairs the vascular reparative response to hindlimb ischemia in a mouse model; clinical relevance to peripheral artery disease. [2021]

3. England pubmed.ncbi.nlm.nih.gov

Unacylated ghrelin is associated with changes in body composition and body fat distribution during long-term exercise intervention. [2016]

4. England pubmed.ncbi.nlm.nih.gov

Pharmacokinetics and pharmacodynamics of PF-05190457: The first oral ghrelin receptor inverse agonist to be profiled in healthy subjects. [2021]

5. Switzerland pubmed.ncbi.nlm.nih.gov

Ghrelin and its relation with N-terminal brain natriuretic peptide, endothelin-1 and nitric oxide in patients with idiopathic pulmonary hypertension. [2015]

6. England pubmed.ncbi.nlm.nih.gov

Effects of ghrelin treatment on exercise capacity in underweight COPD patients: a substudy of a multicenter, randomized, double-blind, placebo-controlled trial of ghrelin treatment. [2021]

7. England pubmed.ncbi.nlm.nih.gov

Effects of acute administration of acylated and unacylated ghrelin on glucose and insulin concentrations in morbidly obese subjects without overt diabetes. [2016]

8. Switzerland pubmed.ncbi.nlm.nih.gov

Des-acyl ghrelin: a metabolically active peptide. [2021]