Ignite Creation Date:
2024-05-06 @ 8:06 PM
Last Modification Date:
2024-10-26 @ 3:20 PM
Study NCT ID:
NCT06258850
Status:
NOT_YET_RECRUITING
Last Update Posted:
2024-02-14
First Post:
2024-02-06
Brief Title:
REstoration of VItamin D in Pulmonary Arterial Hypertension
Sponsor:
Parc de Salut Mar
Organization:
Parc de Salut Mar
Study Overview
Official Title:
REstoration With Calcifediol of VItamin D Deficiency in Pulmonary Arterial Hypertension Patients
Status:
NOT_YET_RECRUITING
Status Verified Date:
2024-02
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
REVIDAH
Brief Summary:
Background Pulmonary arterial hypertension PAH is a heterogeneous pathophysiological condition characterized by progressive pulmonary vascular narrowing that ultimately results in right-sided heart failure and eventually death or lung transplantation The effectiveness of current pharmacological treatments is suboptimal and a large proportion of patients still had events or died despite receiving combination therapy Vitamin D deficiency has been found to be much more frequent in PAH patients than in the general population or even compared to patients with other severe cardiovascular diseases Moreover vitamin D deficiency has a negative prognostic impact in PAH Animal studies support that vitamin D deficiency worsens PAH
Hypothesis In patients with PAH and vitamin D deficiency restoration of vitamin D status with calcifediol improves their symptomatology and prognosis
Design Multicenter clinical trial with the participation of 9 hospitals placebo-controlled randomized 11 ratio in two parallel groups without crossover triple blind and add-on on existing treatments add-on It will include at least 102 subjects 51 in the calcifediol group and 51 in the placebo group followed for 24 weeks of treatment
Inclusion criteria Patients of both sexes 18-75 years with hemodynamic diagnosis of PAH and severe vitamin D deficiency 25-OHvitD 12 ngml and without previous diagnosis of osteoporosis or osteomalacia
Treatments 1 Calcifediol Hydroferol 0266 mg once every 10 days for the first 12 weeks and once every two weeks for the following 12 weeks 2 Placebo
Main objective A composite endpoint of clinical improvement without clinical worsening at week 24
Expected outcome Restoration of vitamin D status is an unexpensive measure very easily implantable and that could improve the evolution of the disease as well as other aspects such as bone or immune health and that has few side effects
Hypothesis In patients with PAH and vitamin D deficiency restoration of vitamin D status with calcifediol improves their symptomatology and prognosis
Design Multicenter clinical trial with the participation of 9 hospitals placebo-controlled randomized 11 ratio in two parallel groups without crossover triple blind and add-on on existing treatments add-on It will include at least 102 subjects 51 in the calcifediol group and 51 in the placebo group followed for 24 weeks of treatment
Inclusion criteria Patients of both sexes 18-75 years with hemodynamic diagnosis of PAH and severe vitamin D deficiency 25-OHvitD 12 ngml and without previous diagnosis of osteoporosis or osteomalacia
Treatments 1 Calcifediol Hydroferol 0266 mg once every 10 days for the first 12 weeks and once every two weeks for the following 12 weeks 2 Placebo
Main objective A composite endpoint of clinical improvement without clinical worsening at week 24
Expected outcome Restoration of vitamin D status is an unexpensive measure very easily implantable and that could improve the evolution of the disease as well as other aspects such as bone or immune health and that has few side effects
Detailed Description:
RESEARCH TEAM PI Diego A Rodríguez Chiaradía Co-PI Francisco Perez-Vizcaino Investigators Joan A Barberá Isabel Blanco Vich Manuel Lopez Meseguer Amaya Martinez Menaca Gregorio M Perez Peñate Raquel López Reyes Alberto García Ortega Jose Andres Tenes Remedios Otero
RATIONALE There is no evidence to support that there is a causal link at least in humans between vitamin D deficiency and PAH Moreover if present the causal relationship might be in either direction vitamin D causingaggravating PAH or PAH inducing vitamin D deficiency Only data from preclinical or small uncontrolled trials are available that suggest that low vitamin D aggravates PH Thus the key clinical question for PAH patients that we are addressing herein is Does restoration of vitamin D levels lead to clinical improvement and better prognosis in PAH patients
Thus our HYPOTHESIS is that in patients with stable PAH and vitamin D deficiency restoration of the vitamin D status with calcifediol supplements improves symptoms and prognosis
MAIN OBJECTIVE To analyze whether a vitamin D supplement 0266 mg calcifediol once every 10 days for the first 12 weeks and once every second week in the following 12 weeks induces clinical improvement without clinical worsening at week 24 compared with placebo
DISEASE The study will be performed in patients with PAH and severe deficit of vitamin D Patients will be at intermediate risk of 1-year mortality according to 2022 European Respiratory Society European Society of Cardiology guidelines despite receiving standard treatment for PAH for at least 6 weeks before randomisation
CLINICAL PHASE Phase IV clinical trial analyzing the therapeutic effects as measured by a composite endpoint of morbidity and mortality of a commercial source of vitamin D Hidroferol 0266 mg available in Spain
PARTICIPATING CENTERS This is a multicentric study that will be conducted in 9 hospital-based pulmonary hypertension centres in Spain
ETHICS AND PATIENT CONSENT The institutional review board at each participating centre will approve the protocol and the study will be carried out in accordance with Good Clinical Practice guidelines and the Declaration of Helsinki All patients will provide written informed consent
STUDY DESIGN Multicentric randomized placebo controlled 11 proportion quadruple blind parallel add-on superiority trial
EXPERIMENTAL DRUG AND ROUTE OF ADMINISTRATION Patients in the active arm will receive oral calcifediol 25-OH vitamin D3 or placebo
DOSING One Hydroferol soft capsule 0266 mg or one placebo capsule will be administered once every 10 days for the first 12 weeks and one capsule every two weeks for the next 12 weeks
ADD-ON At randomization patients must be treated with the standard care including the specific drugs for PAH according to ERSESC guidelines and stable for at least 6 weeks Patients will start the active or placebo treatment and remain with their current PAH treatments
STUDY POPULATION Patients of both sexes and ages between 18 years and 75 years with a diagnosis of PAH and severe vitamin D deficiency
PATIENT RECRUITMENT Patients with a previous diagnosis of PAH stable for the 6 weeks that regularly attend the PH patient outclinic of the participating hospitals will be recruited
DIAGNOSIS of PAH PAH diagnosis according to the 2022 European Society of CardiologyEuropean Respiratory Society guidelines must have been performed in an accredited PH reference unit Therefore patients must present precapillary PH with hemodynamic parameters measured by right heart catheterization of mPAP 20 mmHg pulmonary artery wedge pressure PAWP 15 mmHg and pulmonary vascular resistance PVR 2 WU in the absence of other causes of pre-capillary PH such as chronic thromboembolic PH and PH associated with lung diseases
DEFINITION OF SEVERE VITAMIN D DEFICIENCY The best biomarker of vitamin D status is the serum or plasma level of the hydroxylated form or vitamin D 25OH-cholecalciferol also known as 25OH-vitamin D or calcifediol Although there is no universal consensus on its optimal levels or those representing insufficiency or deficiency most scientific societies and regulatory agencies define vitamin D deficiency as serum or plasma levels of 25OH-vitamin D below 20 ngml According to this ninety-five percent of the patients with PAH in the Spanish cohort showed vitamin D deficiency However patients with the lowest values showed poorer prognosis suggesting that there are important differences depending on the severity of the deficit Therefore patients with the most severe deficiency are expected to be those obtaining greatest benefit There is no widely accepted definition of severe deficiency Herein we will define severe vitamin D deficiency as serum 25OH-vitamin D levels equal to or less than 12 ngml According to this definition and the data of the Spanish PAH cohort we expect that 75 of the otherwise eligible PAH patients will fit into this category This arbitrary cutoff value intends to recruit a large percentage of patients that are expected to have the maximal benefit Therefore patients with values of 12-20 ngml that would potentially obtain marginal benefit will be excluded
RANDOMIZATION Patients will be randomized 11 to placebo the control arm or to Hidroferol active arm A randomization list will be generated using the SAS 9 software for Windows The randomization list will be imported into the REDCap program so that researchers can randomize candidate subjects using a more user-friendly interface Subjects who meet the selection criteria will be randomized between treatment groups in order to achieve balanced randomization in treatment groups The treatment assignment will be centralized thus keeping the sequence hidden
BLINDING AND MASKING Placebo capsules will be identical to those of the active treatment The batch of capsules for each patient will be codified and codes will be provided by the producing company to the SCReN platform who will keep them so that patients and investigators the local pharmacy will be blind
MAIN VARIABLES OF THE STUDY Baseline and 6-month values of the following variables will be compared and be used either for the composite endpoint or as secondary objectives a 6MWD b serum pro-BNP c functional class WHONYAS d noninvasive risk score NIRS based on the three previous variables e ventricular function analyzed echocardiographically by TAPSE and f a mechanistic parameter serum noggin levels difference at 6 months minus baseline In addition quality of life will be compared using the emPHasis-10 questionnaire Echo-doppler will be performed at each hospital and the images will be centrally and blindly analyzed by a single expert echocardiographer
VISITS Visit 0 -2 to -4 weeks Informed consent and eligibility criteria 6MWD functional class and blood sampling for 25OH vitamin D and NT-proBNP Visit 1 week 0 Randomization Visit 2 week 12 Safety analysis of 25OHvitamin D and calcium levels Visit 3 week 24 analysis of efficacy Central phone calls at week 2 4 10 and 20 will be made to assess compliance and possible adverse effects
WITHDRAWAL OF PATIENTS FROM THE STUDY Patients must be withdrawn from study treatment 1 at their own request 2 when in the investigators opinion continuation of the study treatment would be harmful to the patients well-being 3 Occurrence of adverse events AEs or intercurrent diseases which the investigator judges unacceptable for continuation of participation in the study 4 Occurrence of adverse drug reactions which have from the investigators point of view a negative impact on the patients individual risk-benefit ratio 5 Pertinent noncompliance with the conditions for the study or instructions by the investigator 6 In case of pregnancy or breast feeding 7 Participation in another clinical study 8 Patient does not tolerate the experimental drug 9 Patients in the active arm with 25 OH vitamin D levels below 20 ngml or above 100 ngml and patients in the placebo arm with values above 20 ngml in the intermediate safety analysis
RISKS Adverse reactions of hydroferol are generally uncommon 11000 to 1100 although they are sometimes moderately important The most significant adverse effects are related to excessive intake of vitamin D especially when associated with high doses of calcium which is not the case per study protocol The most characteristic adverse reactions are due to the hypercalcaemia
INTERMEDIATE SAFETY ANALYSIS Serum 25OHvitamin D will be centrally analyzed in patients receiving either the active treatment or placebo at 12 weeks The results will be communicated neither to patients nor investigators except for the following cases Patients in the active arm with 25OH vitamin D levels below 20 ngml or above 100 ngml or with hypercalcemia and patients in the placebo arm with values above 20 ngml will be discontinued from the study
STATISTICAL ANALYSIS Sample size Calculations for the present project are based mainly in the REPLACE trial PMID 33773120 The main endpoint in both trials is similar except that clinical improvement is based on two out of four variables now includes TAPSEPASP instead of two out of three We expect that this would lead to an increase in events of 25 in both arms We assume that our placebo group is similar to the REPLACE control group and we expect that the vitamin D group would lead to a clinical improvement similar to that of the riociguat group in REPLACE The rate of clinical improvement without clinical worsening at week 24 was estimated to be 50 for the vitamin D group and 25 for the placebo A sample size of 51 patients per arm was calculated using granmo software with two-sample frequency X² test one-sided alpha005 power08 with an estimated dropout rate of 10
Outcomes All analyses will be performed using the program applied to the SAS statistics version 9 of the SAS system for Windows At the end of the study summaries of the demographic variables and other characteristics of the subjects specified in the data collection notebook will be made according to the two treatment groups Unless otherwise specified all continuous variables shall be summarized using number of patients n mean standard deviation median minimum and maximum Categorical variables shall be described by absolute and relative frequency The statistical analysis plan SAP will be developed and finalized prior to the publication of the database and will describe the populations of subjects to be included in the analyses and the procedures for accounting for missing unused and non-essential data Comparisons between groups will be made using one-sided Fishers exact test Likewise a multivariate analysis of the main outcome will be made using a binary logistic regression analysis Changes on detailed parameters on secondary objectives will be analyzed through suitable methods for repeated measures paired t test or equivalent non-parametric Wilcoxon Rank-Sum test Also between group differences will be performed comparing 24 week vs baseline differences by group This will be checked through t test or Mann-Whitney test depending on the results of the normality tests in the continuous variables Finally repeated measures ANCOVA will be applied to check effects of possible confounding variables
Data Management Plan All the data of the participants related to the study will be recorded in an Electronic Data Collection EDC whose preparation and maintenance will be carried out from the ISCIII Support Platform for Clinical Research SCReN
RATIONALE There is no evidence to support that there is a causal link at least in humans between vitamin D deficiency and PAH Moreover if present the causal relationship might be in either direction vitamin D causingaggravating PAH or PAH inducing vitamin D deficiency Only data from preclinical or small uncontrolled trials are available that suggest that low vitamin D aggravates PH Thus the key clinical question for PAH patients that we are addressing herein is Does restoration of vitamin D levels lead to clinical improvement and better prognosis in PAH patients
Thus our HYPOTHESIS is that in patients with stable PAH and vitamin D deficiency restoration of the vitamin D status with calcifediol supplements improves symptoms and prognosis
MAIN OBJECTIVE To analyze whether a vitamin D supplement 0266 mg calcifediol once every 10 days for the first 12 weeks and once every second week in the following 12 weeks induces clinical improvement without clinical worsening at week 24 compared with placebo
DISEASE The study will be performed in patients with PAH and severe deficit of vitamin D Patients will be at intermediate risk of 1-year mortality according to 2022 European Respiratory Society European Society of Cardiology guidelines despite receiving standard treatment for PAH for at least 6 weeks before randomisation
CLINICAL PHASE Phase IV clinical trial analyzing the therapeutic effects as measured by a composite endpoint of morbidity and mortality of a commercial source of vitamin D Hidroferol 0266 mg available in Spain
PARTICIPATING CENTERS This is a multicentric study that will be conducted in 9 hospital-based pulmonary hypertension centres in Spain
ETHICS AND PATIENT CONSENT The institutional review board at each participating centre will approve the protocol and the study will be carried out in accordance with Good Clinical Practice guidelines and the Declaration of Helsinki All patients will provide written informed consent
STUDY DESIGN Multicentric randomized placebo controlled 11 proportion quadruple blind parallel add-on superiority trial
EXPERIMENTAL DRUG AND ROUTE OF ADMINISTRATION Patients in the active arm will receive oral calcifediol 25-OH vitamin D3 or placebo
DOSING One Hydroferol soft capsule 0266 mg or one placebo capsule will be administered once every 10 days for the first 12 weeks and one capsule every two weeks for the next 12 weeks
ADD-ON At randomization patients must be treated with the standard care including the specific drugs for PAH according to ERSESC guidelines and stable for at least 6 weeks Patients will start the active or placebo treatment and remain with their current PAH treatments
STUDY POPULATION Patients of both sexes and ages between 18 years and 75 years with a diagnosis of PAH and severe vitamin D deficiency
PATIENT RECRUITMENT Patients with a previous diagnosis of PAH stable for the 6 weeks that regularly attend the PH patient outclinic of the participating hospitals will be recruited
DIAGNOSIS of PAH PAH diagnosis according to the 2022 European Society of CardiologyEuropean Respiratory Society guidelines must have been performed in an accredited PH reference unit Therefore patients must present precapillary PH with hemodynamic parameters measured by right heart catheterization of mPAP 20 mmHg pulmonary artery wedge pressure PAWP 15 mmHg and pulmonary vascular resistance PVR 2 WU in the absence of other causes of pre-capillary PH such as chronic thromboembolic PH and PH associated with lung diseases
DEFINITION OF SEVERE VITAMIN D DEFICIENCY The best biomarker of vitamin D status is the serum or plasma level of the hydroxylated form or vitamin D 25OH-cholecalciferol also known as 25OH-vitamin D or calcifediol Although there is no universal consensus on its optimal levels or those representing insufficiency or deficiency most scientific societies and regulatory agencies define vitamin D deficiency as serum or plasma levels of 25OH-vitamin D below 20 ngml According to this ninety-five percent of the patients with PAH in the Spanish cohort showed vitamin D deficiency However patients with the lowest values showed poorer prognosis suggesting that there are important differences depending on the severity of the deficit Therefore patients with the most severe deficiency are expected to be those obtaining greatest benefit There is no widely accepted definition of severe deficiency Herein we will define severe vitamin D deficiency as serum 25OH-vitamin D levels equal to or less than 12 ngml According to this definition and the data of the Spanish PAH cohort we expect that 75 of the otherwise eligible PAH patients will fit into this category This arbitrary cutoff value intends to recruit a large percentage of patients that are expected to have the maximal benefit Therefore patients with values of 12-20 ngml that would potentially obtain marginal benefit will be excluded
RANDOMIZATION Patients will be randomized 11 to placebo the control arm or to Hidroferol active arm A randomization list will be generated using the SAS 9 software for Windows The randomization list will be imported into the REDCap program so that researchers can randomize candidate subjects using a more user-friendly interface Subjects who meet the selection criteria will be randomized between treatment groups in order to achieve balanced randomization in treatment groups The treatment assignment will be centralized thus keeping the sequence hidden
BLINDING AND MASKING Placebo capsules will be identical to those of the active treatment The batch of capsules for each patient will be codified and codes will be provided by the producing company to the SCReN platform who will keep them so that patients and investigators the local pharmacy will be blind
MAIN VARIABLES OF THE STUDY Baseline and 6-month values of the following variables will be compared and be used either for the composite endpoint or as secondary objectives a 6MWD b serum pro-BNP c functional class WHONYAS d noninvasive risk score NIRS based on the three previous variables e ventricular function analyzed echocardiographically by TAPSE and f a mechanistic parameter serum noggin levels difference at 6 months minus baseline In addition quality of life will be compared using the emPHasis-10 questionnaire Echo-doppler will be performed at each hospital and the images will be centrally and blindly analyzed by a single expert echocardiographer
VISITS Visit 0 -2 to -4 weeks Informed consent and eligibility criteria 6MWD functional class and blood sampling for 25OH vitamin D and NT-proBNP Visit 1 week 0 Randomization Visit 2 week 12 Safety analysis of 25OHvitamin D and calcium levels Visit 3 week 24 analysis of efficacy Central phone calls at week 2 4 10 and 20 will be made to assess compliance and possible adverse effects
WITHDRAWAL OF PATIENTS FROM THE STUDY Patients must be withdrawn from study treatment 1 at their own request 2 when in the investigators opinion continuation of the study treatment would be harmful to the patients well-being 3 Occurrence of adverse events AEs or intercurrent diseases which the investigator judges unacceptable for continuation of participation in the study 4 Occurrence of adverse drug reactions which have from the investigators point of view a negative impact on the patients individual risk-benefit ratio 5 Pertinent noncompliance with the conditions for the study or instructions by the investigator 6 In case of pregnancy or breast feeding 7 Participation in another clinical study 8 Patient does not tolerate the experimental drug 9 Patients in the active arm with 25 OH vitamin D levels below 20 ngml or above 100 ngml and patients in the placebo arm with values above 20 ngml in the intermediate safety analysis
RISKS Adverse reactions of hydroferol are generally uncommon 11000 to 1100 although they are sometimes moderately important The most significant adverse effects are related to excessive intake of vitamin D especially when associated with high doses of calcium which is not the case per study protocol The most characteristic adverse reactions are due to the hypercalcaemia
INTERMEDIATE SAFETY ANALYSIS Serum 25OHvitamin D will be centrally analyzed in patients receiving either the active treatment or placebo at 12 weeks The results will be communicated neither to patients nor investigators except for the following cases Patients in the active arm with 25OH vitamin D levels below 20 ngml or above 100 ngml or with hypercalcemia and patients in the placebo arm with values above 20 ngml will be discontinued from the study
STATISTICAL ANALYSIS Sample size Calculations for the present project are based mainly in the REPLACE trial PMID 33773120 The main endpoint in both trials is similar except that clinical improvement is based on two out of four variables now includes TAPSEPASP instead of two out of three We expect that this would lead to an increase in events of 25 in both arms We assume that our placebo group is similar to the REPLACE control group and we expect that the vitamin D group would lead to a clinical improvement similar to that of the riociguat group in REPLACE The rate of clinical improvement without clinical worsening at week 24 was estimated to be 50 for the vitamin D group and 25 for the placebo A sample size of 51 patients per arm was calculated using granmo software with two-sample frequency X² test one-sided alpha005 power08 with an estimated dropout rate of 10
Outcomes All analyses will be performed using the program applied to the SAS statistics version 9 of the SAS system for Windows At the end of the study summaries of the demographic variables and other characteristics of the subjects specified in the data collection notebook will be made according to the two treatment groups Unless otherwise specified all continuous variables shall be summarized using number of patients n mean standard deviation median minimum and maximum Categorical variables shall be described by absolute and relative frequency The statistical analysis plan SAP will be developed and finalized prior to the publication of the database and will describe the populations of subjects to be included in the analyses and the procedures for accounting for missing unused and non-essential data Comparisons between groups will be made using one-sided Fishers exact test Likewise a multivariate analysis of the main outcome will be made using a binary logistic regression analysis Changes on detailed parameters on secondary objectives will be analyzed through suitable methods for repeated measures paired t test or equivalent non-parametric Wilcoxon Rank-Sum test Also between group differences will be performed comparing 24 week vs baseline differences by group This will be checked through t test or Mann-Whitney test depending on the results of the normality tests in the continuous variables Finally repeated measures ANCOVA will be applied to check effects of possible confounding variables
Data Management Plan All the data of the participants related to the study will be recorded in an Electronic Data Collection EDC whose preparation and maintenance will be carried out from the ISCIII Support Platform for Clinical Research SCReN
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
False
Is an FDA AA801 Violation?:
None