Unacylated Ghrelin for Peripheral Arterial Disease

(GIFTII Trial)

No longer 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores whether unacylated ghrelin, a hormone, can help individuals with peripheral artery disease (PAD) walk further by enhancing blood flow and muscle function. Participants will receive either hormone injections or a placebo (a substance with no active ingredient) daily for four months to assess any changes in their walking ability. Individuals diagnosed with PAD who experience symptoms like leg pain when walking might be suitable candidates. As a Phase 2 trial, this research focuses on evaluating the treatment's effectiveness in an initial, smaller group.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that unacylated ghrelin might improve blood vessel health and reduce stress, based on animal studies. These studies suggest it could protect blood vessels without causing major side effects. However, researchers are still gathering solid information about its safety in humans.

This treatment is currently in a mid-stage trial, where it is being tested for safety and effectiveness. It has passed initial safety tests, but more information is needed to understand how well people tolerate it. Prospective participants should know that while the treatment appears promising, its full safety profile is still under investigation. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for peripheral artery disease?

Unacylated ghrelin is unique for treating peripheral arterial disease because it targets the disease in a fresh way by using a hormone that's usually involved in regulating appetite. Most treatments for this condition focus on improving blood flow with medications like antiplatelet agents or statins. However, unacylated ghrelin has a different mechanism of action, potentially improving blood vessel health and reducing inflammation without the need for traditional drugs. Researchers are excited about its potential to offer a new avenue of relief, especially for patients who might not respond well to existing medications.

What evidence suggests that unacylated ghrelin might be an effective treatment for peripheral artery disease?

Research has shown that unacylated ghrelin, which participants in this trial may receive, might aid individuals with peripheral artery disease (PAD) by enhancing blood flow to their arms and legs. Unlike acylated ghrelin, this treatment does not increase appetite or cause insulin resistance. Studies in mice have found that unacylated ghrelin can protect blood vessels from damage due to oxidative stress, an imbalance between harmful molecules and antioxidants. It also appears to improve blood vessel function, potentially reducing plaque buildup. These early findings suggest that unacylated ghrelin could ease walking for people with PAD. ^{2 3 4 5 6}

Who Is on the Research Team?

Mary McDermott, MD

Principal Investigator

Northwestern University

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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]

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]

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]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT04377126

Unacylated Ghrelin to Improve Functioning in PAD GIFT is a pilot, randomized, double-blinded clinical trial that will examine the effects of unacylated ghrelin on walking ability in people with peripheral ...

2. centerwatch.com centerwatch.com/clinical-trials/listings/NCT04377126/unacylated-ghrelin-to-improve-functioning-in-pad?gender=Male&id=698&slug=peripheral-arterial-disease-pad

Unacylated Ghrelin to Improve Functioning in PAD GIFT is a pilot, randomized, double-blinded clinical trial that will examine the effects of unacylated ghrelin on walking ability in people ...

3. grantome.com grantome.com/grant/NIH/R21-AG063076-01

Unacylated Ghrelin to Improve FuncTioning in PAD Unlike acylated ghrelin, unacylated ghrelin does not increase appetite, or cause insulin resistance. The proposed GIFT Trial will provide preliminary data to ...

4. diabetesjournals.org diabetesjournals.org/diabetes/article/64/4/1370/34882/Unacylated-Ghrelin-Induces-Oxidative-Stress

Unacylated Ghrelin Induces Oxidative Stress Resistance in a ... These results indicate that UnAG protects vessels from ROS imbalance in ob/ob mice by rescuing miR-126 expression, thus emphasizing its potential clinical ...

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6387360/

Unacylated Ghrelin Improves Vascular Dysfunction and ... Chronic UnGhr overexpression results in improved vascular function and reduced plaque formation through decreased vascular oxidative stress, without affecting ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT03358355

Unacylated Ghrelin to Improve FuncTioning in PAD: The ... The GIFT pilot study will investigate the optimal subcutaneous dose and safety of subcutaneously administered unacylated ghrelin in older people with peripheral ...