An evaluation of two drugs for treating a familial form of pulmonary arterial hypertension
| ISRCTN | ISRCTN10304915 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN10304915 |
| IRAS number | 1003631 |
| Secondary identifying numbers | STRATOSPHERE223, IRAS 1003631, CPMS 56619 |
- Submission date
- 03/03/2023
- Registration date
- 22/09/2023
- Last edited
- 14/07/2025
- Recruitment status
- Recruiting
- Overall study status
- Ongoing
- Condition category
- Respiratory
Plain English summary of protocol
Background and study aims
Pulmonary arterial hypertension (PAH) is a progressive respiratory condition that causes high blood pressure in the blood vessels that supply blood to the lungs. Current treatments help to manage the symptoms of the disease but do not treat the underlying cause. The condition can occur in families due to an alteration in a gene (a piece of inherited material) called the bone morphogenetic protein type 2 receptor (BMPR2). Currently, there are no therapies that target BMPR2 dysfunction. In a previous study, the study team identified a set of proteins or biological markers (biomarkers) in the blood that regulate BMPR2. In this study, the study team will be using two repurposed drug therapies, hydroxychloroquine and glycerol phenylbutyrate, both of which can change the way BMPR2 is expressed to see if changing the function of BMPR2 is a potential therapy area in PAH.
Who can participate?
Patients aged between 18-75 years old with PAH
What does the study involve?
Participants will be randomised to either active treatment arms:
(T1 = standard of care + hydroxychloroquine; T2 = standard of care + phenylbutyrate)
or control group either:
(C = standard of care + liquid or tablet placebo).
What are the possible benefits and risks of participating?
It is not known whether you will gain any personal benefit from this research. However, information from this study could improve our understanding of the treatment of PAH and help doctors treat patients better in the future.
There are possible risks associated with the following:
ECG
The electrodes (small sticky sensors) may cause slight discomfort when being taken off the skin. Male participants may need to have small patches of hair on the chest shaved to properly connect the electrodes. Some participants may be sensitive to the adhesive pads resulting in itchy red areas where the patches were placed. These will be performed by an experienced member of staff.
Blood sampling
Minor discomfort, light-headedness or irritation, such as redness, tenderness and bruising at the site used to obtain blood. These will be drawn by an experienced member of the research team.
Trial medication
Both drug treatments (hydroxychloroquine and glycerol phenylbutyrate) used in this trial, are prescribed in the UK for licensed indications and are well tolerated. The doses used in this trial are normal treatment doses prescribed and the drug will be prescribed according to BMI. However, individual participants may react differently to the same drug which means that there is a possibility of experiencing some of the side effects of the drug. Details of drug treatment and side effects are provided in the participant information sheet so participants are fully informed. The trial doctor will monitor any side effects regularly and participants will be encouraged to contact sites if they experience any AEs and take appropriate actions where necessary, by ensuring that all SAEs are assessed for relatedness and expectedness and onward notification of all SARs to the Chief Investigator and Sponsor immediately but not more than 24 hours of first notification.
Where is the study run from?
Royal Papworth NHS Foundation (UK)
When is the study starting and how long is it expected to run for?
January 2020 to February 2027
Who is funding the study?
Medical Research Council (MRC)
Who is the main contact?
1. Dr Mark Toshner (CI), mrt34@medschl.cam.ac.uk
2. Ellen Temple (StratosPHere Trial Manager), ellen.temple4@nhs.net
Contact information
Scientific
Victor Phillip Dahdaleh Heart and Lung Research Institute
University of Cambridge
Papworth Rd
Cambridge
CB2 0AY
United Kingdom
 ORCID ID |
0000-0002-3969-6143 |
|---|---|
| Phone | +44 (0)1223 762007 |
| mrt34@medschl.cam.ac.uk |
Public
Clinical Trial Manager
Papworth Trials Unit Collaboration (PTUC)
Royal Papworth Hospital
Papworth Road
Cambridge Biomedical Campus
Cambridge
CB2 0AY
United Kingdom
| Phone | +44 (0)1223 639809 |
|---|---|
| ellen.temple4@nhs.net |
Principal Investigator
University of Cambridge
Heart and Lung Research Institute
Papworth Rd
Cambridge
CB2 0QQ
United Kingdom
| Phone | +44 (0)1223 762007 |
|---|---|
| mrt34@medschl.cam.ac.uk |
Study information
| Study design | Double-blind three-armed response-adaptive randomized controlled study |
|---|---|
| Primary study design | Interventional |
| Secondary study design | Randomised controlled trial |
| Study setting(s) | Hospital |
| Study type | Safety, Efficacy |
| Participant information sheet | Not available in web format, please use the contact details to request a participant information sheet |
| Scientific title | StratosPHere 2: A response-adaptive randomised placebo-controlled phase IIa trial to evaluate hydroxychloroquine and phenylbutyrate in pulmonary arterial hypertension caused by mutations in BMPR2 |
| Study acronym | StratosPHere 2 |
| Study objectives | Pulmonary arterial hypertension (PAH) is a condition in which a narrowing of the blood vessels carrying blood through the lungs puts increased pressure on the heart resulting in it having to work harder to pump blood through the lungs. While current treatments relieve some of the symptoms, they do not stop or reverse the disease in the affected blood vessels. When the disease occurs in families it can be due to an alteration in a gene (a piece of inherited material) called the bone morphogenetic protein type 2 receptor (BMPR2). The purpose of this study is to improve our understanding of increasing BMPR2 as a treatment for people with PAH by testing two drug therapies; hydroxychloroquine and glycerol phenylbutyrate. We know there are different types of BMPR2 and we want to investigate how these different drug work. In a recent trial, the study team identified biological markers ‘biomarkers’ in the blood that regulate BMPR2 and we aim to use these as potential targets for both of these drug therapies. Evaluating the effectiveness of the two drug therapies in a sample of people with a BMPR2 mutation by measuring patient-related outcomes and function specific to this group. |
| Ethics approval(s) |
Approved 12/09/2023, London - Surrey Borders Research Ethics Committee (Equinox House, City Link, Nottingham, NG2 4LA, United Kingdom; +44 (0)207 104 8057, (0)207 104 8104, (0)207 104 8199; surreyborders.rec@hra.nhs.uk), ref: 23/LO/0285 |
| Health condition(s) or problem(s) studied | Pulmonary arterial hypertension |
| Intervention | StratosPHere 2 is a double-blind, three-armed response-adaptive randomised controlled trial of two active arms (T1 = standard of care + hydroxychloroquine; T2 = standard of care + phenylbutyrate) and a control group (C = standard of care + placebo). The adaptation will be performed based on a Bayesian response-adaptive strategy, designed to dynamically allocate more patients in each subgroup to a promising arm if it is showing an earlier positive effect, making efficient use of a small population and giving patients a higher chance of being allocated to the current most efficacious arm of the trial. |
| Intervention type | Drug |
| Pharmaceutical study type(s) | Pharmacogenetic, Pharmacoeconomic |
| Phase | Phase II |
| Drug / device / biological / vaccine name(s) | Hydroxychloroquine, glycerol phenylbutyrate |
| Primary outcome measure | Target engagement of the BMPR2 pathway determined by change in peripheral blood-based BMPR2 function is measured by changes in the expression of a panel of eight BMPR2-modulated genes (i.e., ID3, SMAD1, SMAD5, NOTCH1, NOTCH2, ID2, ARL4C, PTGS2) using quantitative PCR from baseline (study entry/randomisation) to 8 weeks follow-up (8 weeks from treatment initiation) |
| Secondary outcome measures | BMPR2 cell surface protein expression on peripheral blood white cells, measured using flow cytometry at baseline and 8, 16 and 20 weeks |
| Overall study start date | 01/01/2020 |
| Completion date | 01/02/2027 |
Eligibility
| Participant type(s) | Patient |
|---|---|
| Age group | Mixed |
| Lower age limit | 18 Years |
| Upper age limit | 75 Years |
| Sex | Both |
| Target number of participants | 40 |
| Key inclusion criteria | Subjects eligible for enrolment in the study must meet all of the following criteria: 1. Aged between 18-75 years inclusive 2. Weight >40.0 kg at the Screening Visit 3. Having a diagnosis of group 1 PAH due to the following: Idiopathic or Heritable PAH with a known mutation in BMPR2 4. Being stable on an unchanged PAH therapeutic regime for at least 1 month prior to screening 5. Being competent to understand the information given in the approved Informed Consent Form and must sign the form prior to the initiation of any study procedures |
| Key exclusion criteria | PAH treatments: 1. Patients on TNF antagonists or other biological treatments 2. Subject has a known hypersensitivity to the Investigational Products, metabolites, or formulation excipients 3. Subject has a severe renal impairment (creatinine clearance <30 mL/min) at the Screening Visit 4. Subject is currently on either the active treatment arm or trial medication drug class Medical history/current medical conditions: 1. Subject with an active infection at the time of screening 2. Subjects with known Hepatitis B or Tuberculosis 3. Subject has a severe hepatic impairment (Child-Pugh class C with or without cirrhosis) at the screening Visit 4. Patient with ALT or AST >5 x upper limit of normal Haematology and bleeding disorders: 1. Subject has clinically significant anaemia in the opinion of the investigator, in particular from pyruvate kinase and G6PD deficiencies 2. Subjects with bleeding disorders or significant active peptic ulceration in the opinion of the investigator 3. Subject has peripheral blood platelets <100x109/L 4. Subject has a neutrophil count <2x109/L Cardiovascular: 1. Subject has had an acute myocardial infarction within the last 90 days prior to screening General medical conditions: 1. Subject with cardiovascular, liver, renal, haematologic, gastrointestinal, immunologic, endocrine, metabolic, or central nervous system disease that, in the opinion of the Investigator, may adversely affect the safety of the subject and/or efficacy of the investigational product or severely limit the lifespan of the subject other than the condition being studied 2. Subject has a history of malignancies within the past 5 years, except for a subject with localized, non-metastatic basal cell carcinoma of the skin, in situ carcinoma of the cervix, or prostate cancer who is not currently or expected, during the study, to undergo radiation therapy, chemotherapy, and/or surgical intervention, or to initiate hormonal treatment 3. History of known retinal disease 4. Currently taking any of the following contraindicated medications: 4.1. Chloroquine 4.2. Halofantrine 4.3. Amiodarone 4.4. Moxifloxacin 4.5. Cyclosporin 4.6. Mefloquine 4.7. Praziquantel 4.8. Prochlorperazine 4.9. Fluconazole 4.10. Penicillamine 4.11. Ivabridine General Criteria: 1. Female subject who is pregnant or breastfeeding 2. Subject has demonstrated noncompliance with previous medical regimens 3. Subject has a recent (within 1 year) history of abusing alcohol or illicit drugs 4. Subject has participated in a clinical study involving another investigational drug or device within 4 weeks before the Screening Visit |
| Date of first enrolment | 11/12/2023 |
| Date of final enrolment | 01/11/2026 |
Locations
Countries of recruitment
- England
- Scotland
- United Kingdom
Study participating centres
Cambridge Biomedical Campus
Cambridge
CB2 0AY
United Kingdom
Clydebank
G81 4DY
United Kingdom
London
NW3 2QG
United Kingdom
Sheffield
S5 7AU
United Kingdom
Hammersmith
London
W12 0HS
United Kingdom
High Heaton
Newcastle upon Tyne
NE7 7DN
United Kingdom
London
SW3 6NP
United Kingdom
Bath
BA1 3NG
United Kingdom
Sponsor information
Hospital/treatment centre
Papworth Rd
Cambridge
CB2 0BB
United Kingdom
| Phone | +44 (0)1223 639678 |
|---|---|
| papworth.randdenquiries@nhs.net | |
| Website | https://royalpapworth.nhs.uk/research-and-development |
"ROR" |
https://ror.org/01qbebb31 |
Funders
Funder type
Research council
Government organisation / National government
- Alternative name(s)
- Medical Research Council (United Kingdom), UK Medical Research Council, MRC
- Location
- United Kingdom
Results and Publications
| Intention to publish date | 31/10/2027 |
|---|---|
| Individual participant data (IPD) Intention to share | No |
| IPD sharing plan summary | Data sharing statement to be made available at a later date |
| Publication and dissemination plan | 1. Peer reviewed scientific journals 2. Conference presentation 3. Publication on website 4. Submission to regulatory authorities 5. Anonymised data will be shared with other researchers in the form of publications and at conferences. This will be explicitly detailed in the patient information sheet and discussed with the participant during entry onto the study. |
| IPD sharing plan | The data-sharing plans for the current study are unknown and will be made available at a later date |
Study outputs
| Output type | Details | Date created | Date added | Peer reviewed? | Patient-facing? |
|---|---|---|---|---|---|
| Protocol article | 15/10/2024 | 17/10/2024 | Yes | No | |
| Statistical Analysis Plan | 11/07/2025 | 14/07/2025 | No | No |
Editorial Notes
14/07/2025: Publication reference added.
17/10/2024: Publication reference added.
05/09/2024: The public contact was updated.
14/12/2023: The recruitment start date was changed from 15/12/2023 to 11/12/2023.
21/11/2023: The recruitment start date was changed from 01/11/2023 to 15/12/2023.
04/10/2023: Internal review.
03/03/2023: Trial's existence confirmed by Health Research Authority (HRA) (UK).
