ATLAS Therapy for Intermittent Claudication

(ATLAS Trial)

Overseen By Shauneen Valliere, MSN

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: University of Massachusetts, Worcester

Must not be taking: PDE3 inhibitors, PDE5 inhibitors

Disqualifiers: Hypotension, Critical leg ischemia, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 90 days

10 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new treatment called ATLAS Therapy, a form of supervised exercise therapy, for individuals with peripheral arterial disease who experience claudication, or leg pain during walking due to poor blood flow. Researchers aim to determine if this therapy can increase Nitric Oxide levels in the blood, potentially enabling patients to walk further without pain and enhancing their overall activity levels. Participants will receive a combination of supplements, including Tetrahydrobiopterin, in two different doses throughout the study. Individuals experiencing leg pain from claudication and willing to discontinue certain medications might be suitable for this trial. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants a chance to be among the first to receive this new therapy.

Will I have to stop taking my current medications?

Yes, you will need to stop taking certain medications, specifically phosphodiesterase (PDE) 5 inhibitors like Viagra and Cialis, and PDE 3 inhibitors like cilostazol. The trial requires participants to discontinue these medications.

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

Research has shown that Tetrahydrobiopterin, used in ATLAS Therapy, is generally well-tolerated by patients. In one study, researchers closely monitored safety and found no major side effects, suggesting the treatment is relatively safe for humans.

Tetrahydrobiopterin has also been studied for other conditions and is often used to improve blood flow. Overall, the available evidence supports the idea that this treatment is safe for people to try in clinical trials. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Unlike the standard treatments for intermittent claudication, which typically include medications like cilostazol and lifestyle changes such as exercise therapy, ATLAS Therapy uses Tetrahydrobiopterin (BH4) to target the condition differently. BH4 is involved in the production of nitric oxide, which helps improve blood flow and reduces symptoms of intermittent claudication. Researchers are excited because this approach could directly enhance blood vessel function and offer a novel way to manage the condition more effectively than current options. Additionally, the use of combined doses with l-Ascorbate and l-Arginine might boost the overall effectiveness of the treatment.

What evidence suggests that this trial's treatments could be effective for intermittent claudication?

Research has shown that a combination of Tetrahydrobiopterin, l-Arginine, and l-Ascorbate might improve blood flow in the legs for individuals with peripheral arterial disease. This mix is believed to increase the production of Nitric Oxide, a substance that can widen blood vessels and enhance circulation. Previous studies have found that higher Nitric Oxide levels are linked to better leg function and less pain while walking. In this trial, participants will receive varying doses of Tetrahydrobiopterin alongside l-Arginine and l-Ascorbate to assess its effectiveness. Early results suggest that ATLAS Therapy, which participants in this trial may receive, could help individuals walk longer distances without pain. The aim is to determine if these improvements can lead to increased overall physical activity. ^{1 2 4 6 7}

Who Is on the Research Team?

Louis M Messina, MD

Principal Investigator

UMASS Medical School

Are You a Good Fit for This Trial?

Adults over 18 with claudication from peripheral arterial disease (PAD) can join this trial if they have an Ankle-Brachial Index (ABI) <0.9, agree to stop certain medications like Viagra and Cilostazol, and use contraception if sexually active. Excluded are those with severe blood pressure issues, recent heart attacks or strokes, critical leg ischemia, kidney/liver problems, history of seizures or stones in the kidney.

Inclusion Criteria

I am older than 18 years.

I am willing to use birth control during the study.

Willing and able to provide informed consent

Exclusion Criteria

I have had a seizure before.

I need treatment with a drug that affects vitamin B9 use.

I have a severe illness like COPD or heart failure that makes it hard for me to walk.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive ATLAS Therapy with two different doses of Tetrahydrobiopterin over 90 days

90 days

Regular visits for monitoring and dose adjustments

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• ATLAS Therapy

Trial Overview The study tests whether a combination therapy including Tetrahydrobiopterin at two different doses along with L-Ascorbate and L-Arginine can boost Nitric Oxide production in the blood. This could potentially improve walking distance without pain for those with PAD.

How Is the Trial Designed?

Group I: Tetrahydrobiopterin Dose 2 (Day 45 to 90) Experimental Treatment 3 Interventions

All subjects will receive 3300mg l-Ascorbate, l-Arginine 3400mg and 20mg/kg of Tetrahydrobiopterin once a day.

Group II: Tetrahydrobiopterin Dose 1 (Day 0 to 44) Experimental Treatment 3 Interventions

All subjects will receive 3300mg l-Ascorbate , l-Arginine 3400mg and 10mg/kg of Tetrahydrobiopterin once a day.

ATLAS Therapy is already approved in European Union, United States for the following indications:

Approved in European Union as Exercise Therapy for Intermittent Claudication for:

• Peripheral Arterial Disease
• Intermittent Claudication

Approved in United States as Supervised Exercise Therapy for:

• Peripheral Artery Disease
• Intermittent Claudication

Who Is Running the Clinical Trial?

University of Massachusetts, Worcester

Lead Sponsor

Trials

372

Recruited

998,000+

Louis Messina

Lead Sponsor

Trials

1

Recruited

10+

National Institute on Aging (NIA)

Collaborator

Trials

1,841

Recruited

28,150,000+

BioMarin Pharmaceutical

Industry Sponsor

Trials

162

Recruited

115,000+

Alexander Hardy

BioMarin Pharmaceutical

Chief Executive Officer since 2023

MBA from INSEAD

Greg Friberg

BioMarin Pharmaceutical

Chief Medical Officer

MD from New York Medical College

Published Research Related to This Trial

Supervised exercise therapy (SET) significantly improves walking distance and quality of life in patients with intermittent claudication compared to just 'go home and walk' advice, with a median increase in walking distance of 310 meters for SET and 360 meters for SET with feedback after 12 months.

Providing daily feedback with an accelerometer alongside SET did not lead to additional improvements in walking distance or quality of life, suggesting that the structured exercise itself is the key factor in enhancing patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Multicenter randomized clinical trial of supervised exercise therapy with or without feedback versus walking advice for intermittent claudication. Nicolaï, SP., Teijink, JA., Prins, MH.[2015]

Supervised exercise therapy (SET) significantly improves maximal walking distance (MWD) and pain-free walking distance (PFWD) in patients with intermittent claudication compared to home-based exercise therapy (HBET) and walking advice (WA), with increases of approximately 120 and 210 meters after three months, respectively.

SET shows better outcomes for self-reported functional impairment and some quality of life measures compared to WA, while HBET does not demonstrate significant improvements over WA, indicating that SET is the most effective exercise intervention for enhancing walking capacity in these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Supervised exercise therapy versus home-based exercise therapy versus walking advice for intermittent claudication. Hageman, D., Fokkenrood, HJ., Gommans, LN., et al.[2022]

The Network Exercise Therapy Parkstad has successfully trained 27 physiotherapists from 22 practices to provide supervised exercise therapy (ET) for patients with intermittent claudication, improving access to care in the Netherlands.

A web-based database has been established to facilitate communication between physiotherapists and vascular surgeons, ensuring continuous updates on patient information and enabling better monitoring of patient performance and safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The development and implementation of a regional network of physiotherapists for exercise therapy in patients with peripheral arterial disease, a preliminary report. Willigendael, EM., Bendermacher, BL., van der Berg, C., et al.[2018]

Supervised walking therapy (SWT) significantly improves maximum walking distance (MWD) by an average of 180 meters and pain-free walking distance (PFWD) by 128 meters in patients with intermittent claudication, based on a meta-analysis of 25 randomized controlled trials involving 1054 patients.

Despite the effectiveness of SWT, the study found that specific exercise components such as intensity, duration, or content did not independently contribute to improvements in walking distances, suggesting that the overall approach of supervised walking is what matters most.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Supervised walking therapy in patients with intermittent claudication. Fakhry, F., van de Luijtgaarden, KM., Bax, L., et al.[2022]

In a study of 420 patients with intermittent claudication, compliance with supervised exercise therapy guidelines was found to be 80.5%, indicating a relatively high adherence to recommended treatments.

Most deviations from the guidelines (15.7%) were justified as providing personalized care, suggesting that while some variation exists, it often aims to meet individual patient needs rather than being unjustified.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real World Practice Deviation from Nationwide Guidelines in Patients with Intermittent Claudication. Aaij, AGL., Wermelink, B., Haalboom, M., et al.[2021]

Exercise therapy significantly improves pain-free walking distance (PWD) and absolute walking distance (AWD) in patients with intermittent claudication, based on a systematic review of 15 studies involving 761 patients.

Supervised exercise therapy is more effective than standard care, showing an increase in PWD by 81.3 meters and AWD by 155.8 meters, but the added benefit of supervision over unsupervised exercise needs further investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Exercise therapy and the additional effect of supervision on exercise therapy in patients with intermittent claudication. Systematic review of randomised controlled trials. Wind, J., Koelemay, MJ.[2022]

Home-based exercise programs (HBEPs) for individuals with intermittent claudication (IC) are safe, with only four adverse events reported over 147,810 patient-hours, resulting in a complication rate of one event per 36,953 patient-hours.

Most adverse events were cardiac-related and occurred during high levels of claudication pain, suggesting that while HBEPs are generally safe, monitoring and possibly cardiac screening may be beneficial for those engaging in more intense exercise.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety of home-based exercise for people with intermittent claudication: A systematic review. Waddell, A., Seed, S., Broom, DR., et al.[2022]

A survey of 84 vascular surgeons in the UK revealed that only 24% had access to supervised exercise programs for patients with intermittent claudication, despite strong recommendations for such programs from major clinical guidelines.

The study highlights a significant gap between evidence-based recommendations and actual practice, with 72% of respondents citing lack of resources as a barrier to implementing supervised exercise, which is known to improve patient outcomes and quality of life.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Supervised exercise for intermittent claudication - an under-utilised tool. Shalhoub, J., Hamish, M., Davies, AH.[2022]

Supervised exercise therapy (SET) for patients with intermittent claudication (IC) is very safe, with only eight adverse events reported over 82,725 hours of training, resulting in a complication rate of just one event per 10,340 patient-hours.

The study suggests that routine cardiac screening before starting SET is unnecessary, which may encourage more healthcare providers to recommend this effective treatment for IC patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety of supervised exercise therapy in patients with intermittent claudication. Gommans, LN., Fokkenrood, HJ., van Dalen, HC., et al.[2022]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11904498/

Nutritional L-Citrulline and Tetrahydrobiopterin in Peripheral ... Currently, the primary treatment for intermittent claudication is physical therapy, that is, physical exercise with intermittent walking., ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT03493412

Effects of Tetrahydrobiopterin (BH4) on Leg Blood Flow ... Therefore, the purpose of this proposed study will be to examine the effects of BH4 on vascular function, oxidative stress and leg performance in patients with ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC3172060/

Is tetrahydrobiopterin a therapeutic option in diabetic ... The aim of this paper is to review the rationale for therapeutic strategies directed to biopterins as a target for vascular disease in type 2 diabetic ...

4. centerwatch.com centerwatch.com/clinical-trials/listings/NCT03493412/effects-of-tetrahydrobiopterin-bh4-on-leg-blood-flow-and-exercise-capacity-in-patients-with-peripheral-artery-disease?activelyRecruiting=false&page=119&id=391&slug=claudication

Effects of Tetrahydrobiopterin (BH4) on Leg Blood Flow ... Therefore, the purpose of this proposed study will be to examine the effects of BH4 on vascular function, oxidative stress and leg performance ...

5. clinicaltrials.biomarin.com clinicaltrials.biomarin.com/clinical-trial/the-effects-of-atlas-therapy-on-nitric-oxide-bioavailability-in-patients-with-intermittent-claudication/

The Effects of ATLAS Therapy on Nitric Oxide ... This study will focus on people with claudication from peripheral arterial disease. The investigators are researching whether a multicomponent therapeutic can ...

6. jacc.org jacc.org/doi/abs/10.1016/j.jacadv.2025.101590

Nutritional L-Citrulline and Tetrahydrobiopterin in ... This randomized, placebo-controlled, double-blinded crossover interventional trial aims to measure the effect of L-citrulline and tetrahydrobiopterin (H4Bip) on ...

7. biomarin.com biomarin.com/news/press-releases/results-from-phase-2-clinical-study-of-6r-bh4-in-peripheral-arterial-disease-not-statistically-significant/

Results From Phase 2 Clinical Study of 6R-BH4 in ... Endothelial dysfunction evaluated by peripheral arterial tonometry in a subset of patients did not show a significant benefit with 6R-BH4.