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Trial registered on ANZCTR


Registration number
ACTRN12614000418673
Ethics application status
Approved
Date submitted
10/04/2014
Date registered
16/04/2014
Date last updated
22/12/2020
Date data sharing statement initially provided
1/04/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Scleroderma-Pulmonary Arterial Hypertension Intervention with Apixaban: The SPHInX Study
Scientific title
A multi-centre, double-blind, randomised, placebo-controlled
trial, of oral anticoagulation with apixaban in participants with Systemic Sclerosis-related Pulmonary Arterial Hypertension, measuring time to clinical worsening of Pulmonary Arterial Hypertension.
Secondary ID [1] 284351 0
Nil
Universal Trial Number (UTN)
U1111-1155-0511
Trial acronym
SPHInX
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Systemic Sclerosis 291505 0
Pulmonary Arterial Hypertension 291506 0
Condition category
Condition code
Inflammatory and Immune System 291876 291876 0 0
Connective tissue diseases
Inflammatory and Immune System 292045 292045 0 0
Autoimmune diseases
Cardiovascular 292046 292046 0 0
Hypertension

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The study drug, apixaban 2.5mg, will be administered orally in the form of a reddish brown, plain, oval shaped, shallow bi-convex film coated tablet, twice daily for 3 years.

Participants will keep a diary to record any missed dose and adherence to the intervention will be monitored by counting unused tablets at study follow-up visits.
Intervention code [1] 289078 0
Treatment: Drugs
Comparator / control treatment
The comparator will be a placebo, administered orally in the form of a reddish brown, plain, oval shaped, shallow bi-convex film coated tablet, twice daily for 3 years.

Participants will keep a diary to record any missed dose and adherence to the intervention will be monitored by counting unused tablets at study follow-up visits.
Control group
Placebo

Outcomes
Primary outcome [1] 291797 0
Time to first clinical worsening, defined as time from Randomisation to the first of the following events:
1. Death (all-cause mortality), or
2. Hospitalization for worsening of PAH based on predefined criteria:
2.1 need for lung transplantation or balloon atrial septostomy, or
2.2 initiation of parenteral (subcutaneous and intravenous) prostanoid therapy or chronic oxygen therapy due to worsening of PAH, or
3. Disease progression defined by the combination of at least TWO of the three following components:
3.1 decrease in 6MWD from Baseline (greater than or equal to 15%, confirmed by 2 tests on different days ideally within 2 weeks), and/or
3.2 worsening of PAH symptoms, must include at least one of the following: NYHA/WHO functional class increased unless NYHA/WHO functional class IV at Baseline,
or appearance or worsening of signs/symptoms of right heart failure;
and/or
3.4 need for additional PAH specific therapythat may include the following:
i) inhaled prostanoids (eg. Iloprost)
ii) oral phosphodiesterase inhibitors (eg. sildenafil)
iii) endothelin receptor antogonists (eg. bosentan)
iv) intravenous diuretics.
Timepoint [1] 291797 0
Time from Randomisation up to 30 days after last study drug intake or 36 month end of study visit.
Secondary outcome [1] 307567 0
The total number of clinical worsening events, as defined in the primary endpoint of the study, adjudicated by a blinded Endpoint Analysis Committee
Timepoint [1] 307567 0
at 3 years after randomisation.
Secondary outcome [2] 307568 0
Change in 6-minute walk distance
Timepoint [2] 307568 0
from Baseline to each of 12, 24 and 36 months after randomisation.
Secondary outcome [3] 307569 0
Absence of worsening in modified NYHA/WHO functional class
Timepoint [3] 307569 0
from Baseline to each of 12, 24 and 36 months after randomisation.
Secondary outcome [4] 307570 0
Change in Borg dyspnoea index
Timepoint [4] 307570 0
from Baseline to each of 12, 24 and 36 months after randomisation.
Secondary outcome [5] 307571 0
Mortality (all cause).
Timepoint [5] 307571 0
at 12, 24 and 36 months (adjusted for time since diagnosis of PAH).
Secondary outcome [6] 307572 0
Change in the ‘Symptoms’, ‘Activity’ and ‘QoL’ scores in the CAMPHOR (Cambridge Pulmonary Hypertension Outcome Review) questionnaire.
Timepoint [6] 307572 0
from Baseline to each of 12, 24 and 36 months after randomisation.
Secondary outcome [7] 307573 0
Change in the SF36 score
Timepoint [7] 307573 0
from Baseline to each of 12, 24 and 36 months after randomisation.
Secondary outcome [8] 307574 0
Change in the Scleroderma Health Assessment Questionnaire score
Timepoint [8] 307574 0
from Baseline to each of 12, 24 and 36 months after randomisation.

Eligibility
Key inclusion criteria
Eligible patients must meet all of the following inclusion criteria:
1. Signed informed consent prior to initiation of any study-mandated procedure.

2. Male and female patients aged from 18 years to 75 years inclusive, with symptomatic permissible Group 1 pulmonary hypertension (PH) subcategories limited to
2.1 Idiopathic PAH
2.2 Heritable PAH, including genetic mutations in BMPR2, ALK-1, ENG, SMAD9, CAV1, KCNK3 or unknown
2.3 Associated with CTD such as:
2.3.1 Scleroderma as defined by the ACR/EULAR criteria for SSc
2.3.2 Systemic lupus erythematosus (SLE) patients that fulfill either the ACR or Systemic Lupus International Collaborating Clinics (SLICC) classification criteria for SLE
2.3.3 Mixed connective tissue disease
2.3.4 Rheumatoid or psoriatic arthritis
2.3.5 Dermatomyositis
2.3.6 Sjogren’s syndrome

3. PAH diagnosed by right heart catheterization (RHC). The RHC diagnosis may be at any time prior to baseline. The RHC must show:
3.1 Resting mean pulmonary arterial pressure (mPAP) greater than or equal to 25 mmHg,and
3.2 Resting pulmonary vascular resistance (PVR) greater than or equal to 3 woods units, and
3.3 Resting pulmonary capillary wedge pressure (PCWP) or left ventricular end diastolic pressure (LVEDP) less than or equal to 15 mmHg, or if PVR cannot or has not been measured, then mPAP greater than or equal to 30 mmHg with PCWP or LVEDP less than or equal to 15 mmHg.

4. 6-minute walk distance (6MWD) greater than 50 meters at Screening/Baseline.

5. Other causes of PAH, in particular Chronic Thromboembolic Pulmonary Hypertension (CTEPH) must have been previously excluded by either a VQ scan or CT pulmonary angiography.

6. Currently taking at least one of the following medications in a stable dose for the 2 months prior to baseline visit: an endothelin antagonist (either bosentan, ambrisentan or macitentan) and/or a PDE-5 inhibitor (sildenafil or tadalafil).

7. Female subjects of childbearing potential must test negative for pregnancy.

8. Male and female subjects of childbearing potential must agree to use a highly effective method of contraception throughout the study and for at least 28 days after the last dose of the study drug. A subject is of childbearing potential if, in the opinion of the investigator, he/she is biologically capable of having children and is sexually active.

9. Female subjects who are not of childbearing potential must meet at least one of the following criteria
9.1 Have undergone documented hysterectomy and/or bilateral oophorectomy
9.2 Have medically confirmed ovarian failure or;
9.3 Achieved postmenopausal status, defined as: cessation of regular menses for at least 12 consecutive months with no alternative pathological or physiological cause and have a serum follicle-stimulation hormone (FSH) level within the laboratory’s reference range for post-menopausal females.
Minimum age
18 Years
Maximum age
75 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Patients will not be entered into the study if they meet any of the following criteria:
1. Patients with pulmonary hypertension (PH) due to any other cause other than idiopathic, heritable or CTD-PAH.

2. Patients with moderate or severe obstructive lung disease:
FEV1/FVC < 70% and FEV1 < 65% of predicted value after bronchodilator administration.

3. Patients with moderate or severe restrictive lung disease:
FVC < 70% of predicted value, provided that HRCT demonstrates moderate to severe changes of ILD; or FVC < 60% of predicted value, regardless of ILD on HRCT.

4. Patients with moderate or severe hepatic impairment (Child-Pugh B and C).

5. Patients with documented left ventricular dysfunction (i.e. ejection fraction < 45%)

6. Patients with severe renal insufficiency (estimated creatinine clearance < 25 mL/min, or serum creatinine > 200 µmol/L).

7. Patients who are receiving or have been receiving any investigational drugs within 1 month before the Baseline Visit.

8. Patients receiving continuous intravenous epoprostenol or iloprost at the Screening or Baseline Visits or be planned to initiate this therapy within the next 3 months.

9. Psychotic, addictive or other disorder limiting the ability to provide informed consent or to comply with study requirements.

10. Life expectancy due to another condition of less than 12 months.

11. Females who are lactating or pregnant (positive pre-randomization serum pregnancy test) or plan to become pregnant during the study.

12. Known hypersensitivity to drugs of the same class as the study drug, or any of the excipients of the drug formulations.

13. Patient with GIT bleeding in the last 12 months due to gastric antral vascular ectasia (GAVE) or unexplained iron deficiency anemia (in the last 12 months).

14. Patients with Hb <10.0 g/dL at Screening.

15. Patients with significant falls risk in whom anticoagulation would be inappropriate.

16. Patients who have received any oral or subcutaneous anticoagulants (e.g. warfarin, apixaban, rivaroxaban, dabigatran, enoxaparin, dalteparin or heparin) for more than 3 months since the diagnosis of PAH.

17. Patients with a prosthetic valve who require long term oral anticoagulation.

18. Patients who are currently in atrial fibrillation.

19. Patients with PAH not on either an ETRA or PDE-5 inhibitor.

20. Patients with known bleeding disorders and/or Platelet count < 100 at screening visit and/or INR >1.2 at screening visit.

21. Brain, spinal or eye surgery within the last one month.

22. Uncontrolled Systemic Hypertension defined as either systolic BP at screening >179mmHg or diastolic BP >109 mmHg.

23. Documented episode of either Pulmonary embolus or Deep venous thrombosis since diagnosis of PAH on RHC.

24. Patients with a current, or active in the last one month, major bleed that is life threatening, causes chronic sequelae or consumes major health care resources, ie. symptomatic bleeding in a critical area or organ, such as intracranial, intraspinal, intraocular, retroperitoneal, intra-articular or pericardial, intramuscular with compartment syndrome, or bleeding causing a fall in Hb greater than or equal to 20g/L leading to transfusion of two or more units of whole blood or red cells.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Investigators will enrol subjects during routine clinical assessments and phone the central pharmacy that holds the randomisation schedule, for allocation of treatment.

This study is performed in a double-blind fashion. The investigators and study staff and the subjects will remain blinded to the treatment until study closure. The investigational drug and its matching placebo will be indistinguishable and all treatment kits will be packaged in the same way.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Block randomisation using computerised sequence generation software, stratified by study site.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
If the subject experiences a medical emergency wherein management would be improved by the knowledge of the blinded treatment assignment, unblinding will be available 24 Hours per day. The Principal Investigator (PI) at each site responsible for the subject will be the first point of contact. If he/she deems it necessary to unblind treatment assignment, he/she (or a delegate) will contact the rostered Chief Investigator (CI), MN, WS, DP or HN, at the study coordinating site (SVHM), who will have 24 hours a day access to the blinding codes.

Unblinded subjects will be withdrawn from the study and will complete an EOS visit as soon as possible after unblinding. A log of every access to the unblinding codes will be kept. The request for unblinding of any subject during the study must be clearly justified and explained by the investigator requesting the code break and documented in the CRF. In addition a set of tamper-proof sealed envelopes containing the blinding code for each subject will be kept at each site in case contact with the rostered CI at SVHM for some reason fails. The integrity of these sealed envelopes will be periodically checked.
Phase
Phase 3
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
Protocol deviations will be identified by medically-trained staff before the Study Closure. There will be no interim efficacy analyses and all analyses for efficacy will be undertaken at the end of the study. All statistical analyses will be performed using STATA software (Version 12).

Subjects without a valid or substituted post-baseline value for a particular endpoint will be excluded from the relevant analysis. Four analysis sets are defined:
1. Intention to treat = all randomised subjects, whether or not they received study drug.
2. All treated = all randomised subjects who received at least one dose of the study drug.
3. Safety set = randomised subjects who received at least one dose of the study drug, and had at least one assessment visit post-baseline.
4. Per-protocol set = all randomised subjects who received at least one dose of the study drug and did not violate the protocol in a way that might affect the evaluation of the effect of the study drug on the primary endpoint, ie. without major protocol violations.

The ratio of the hazards of a clinical worsening event in the two groups is not expected to change over time. Therefore, the use of methods requiring proportional hazards is considered appropriate.

The following hypothesis will be tested:
Null hypothesis (H0): The distribution of the primary endpoint is the same in the treatment groups.

Alternative hypothesis (H1): The distribution of the primary endpoint in the placebo group differs from the distribution in the active group.

The difference to be detected is a hazard ratio placebo/treatment of 2.0.
Type I error: alpha = 0.05 (2-sided)
Type II error: beta = 0.2 (power = 80%)

The null hypothesis will be tested by means of the log-rank test. No adjustment for covariates is planned for the primary analysis. Clinical worsening up to 30 days after last study drug intake will be counted for the analysis of the primary endpoint. Subjects without clinical worsening event permanently discontinuing treatment will be censored 30 days after study treatment discontinuation. The time to occurrence of the first clinical worsening event up to 30 days after the last study drug intake will be described by Kaplan Meier curves. 95% confidence intervals of the event-free proportion estimates at relevant time-points will be presented for each treatment group in graphical and tabular form. The hazard ratio of placebo/treatment with its 95% two-sided confidence limits will also be computed.

We expect a drop-out/withdrawal rate of 10% over the duration of the study. The primary analysis set will be the all-randomised set (intention-to-treat analysis). In order to evaluate the robustness of results, the primary endpoint will be analyzed on the Per-protocol set.

Supportive analyses will be conducted using appropriate covariates (e.g., the start date of concomitant PAH medications) in a Cox regression model.

Sample size calculation was based on the comparison of two survival curves for the primary outcome variable, according to the method of Rubinstein. The following variables were used: (i) alpha=0.05, two-sided; (ii) beta=0.2 (power 80%); (iii) delta (hazard ratio of control:exposed) = 2.0; this was based on the effect size seen in our observational study, but reduced by 75% for the purposes of an RCT to provide a more conservative estimate. It is expected that 65 events will be observed in this study. As previously discussed, several other observational studies have found a similar 2- to 3-fold survival benefit over 3 years with anticoagulation in SSc-PAH (44-47) (iv) control group median survival = 45.6 months; this was taken from our observational study; (v) ratio of subjects randomised to control and experimental groups = 1:1 (vi) block randomisation according to 13 centres; (vii) duration of recruitment = 24 months; (viii) duration of follow-up = 36 months; (ix) expected attrition = 10%; however, substantial loss to follow-up is unlikely as subjects are required to attend for regular review in order to continue receiving PBS-subsidised PAH therapy. Based on these variables, our required sample size in each of two groups is 85, making a total of 170 patients. Power considerations are determined using STATA software (Version 12.0).

Recruitment
Recruitment status
Active, not recruiting
Date of first participant enrolment
Anticipated
1/06/2014
Actual
8/09/2014
Date of last participant enrolment
Anticipated
28/06/2019
Actual
22/02/2019
Date of last data collection
Anticipated
31/07/2022
Actual
Sample size
Target
170
Accrual to date
Final
28
Recruitment in Australia
Recruitment state(s)
NSW,QLD,SA,TAS,WA,VIC
Recruitment hospital [1] 2261 0
The Queen Elizabeth Hospital - Woodville
Recruitment hospital [2] 2262 0
Royal Prince Alfred Hospital - Camperdown
Recruitment hospital [3] 2263 0
The Royal Adelaide Hospital - Adelaide
Recruitment hospital [4] 2266 0
Monash Medical Centre - Clayton campus - Clayton
Recruitment hospital [5] 2267 0
Liverpool Hospital - Liverpool
Recruitment hospital [6] 2331 0
St Vincent's Hospital (Melbourne) Ltd - Fitzroy
Recruitment hospital [7] 3803 0
Royal Hobart Hospital - Hobart
Recruitment hospital [8] 3805 0
Gold Coast Hospital - Southport
Recruitment hospital [9] 3819 0
Mid-North Coast Arthritis Clinic - Coffs Harbour
Recruitment hospital [10] 3821 0
Institute for Respiratory Health - Nedlands
Recruitment hospital [11] 7897 0
Princess Alexandra Hospital - Woolloongabba
Recruitment hospital [12] 13527 0
St Vincent's Hospital (Darlinghurst) - Darlinghurst
Recruitment postcode(s) [1] 7926 0
6009 - Nedlands
Recruitment postcode(s) [2] 7927 0
5000 - Adelaide
Recruitment postcode(s) [3] 7928 0
4558 - Maroochydore
Recruitment postcode(s) [4] 7929 0
7000 - Hobart
Recruitment postcode(s) [5] 7930 0
2050 - Camperdown
Recruitment postcode(s) [6] 7931 0
3168 - Clayton
Recruitment postcode(s) [7] 7933 0
5011 - Woodville
Recruitment postcode(s) [8] 7935 0
1871 - Liverpool
Recruitment postcode(s) [9] 7936 0
2450 - Coffs Harbour
Recruitment postcode(s) [10] 7937 0
3065 - Fitzroy
Recruitment postcode(s) [11] 9691 0
4215 - Southport
Recruitment postcode(s) [12] 15853 0
4102 - Woolloongabba
Recruitment postcode(s) [13] 26147 0
2010 - Darlinghurst

Funding & Sponsors
Funding source category [1] 288988 0
Government body
Name [1] 288988 0
National Health and Medical Research Council
Country [1] 288988 0
Australia
Primary sponsor type
Hospital
Name
St Vincent's Hospital Melbourne Pty Ltd
Address
Rheumatology Department
St Vincent's Hospital Melbourne
PO Box 2900
Fitzroy VIC 3065
Country
Australia
Secondary sponsor category [1] 287668 0
None
Name [1] 287668 0
Address [1] 287668 0
Country [1] 287668 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 290798 0
St Vincent's Hospital Melbourne Human Research Ethics Committee D (EC00343)
Ethics committee address [1] 290798 0
Ethics committee country [1] 290798 0
Australia
Date submitted for ethics approval [1] 290798 0
26/03/2014
Approval date [1] 290798 0
12/05/2014
Ethics approval number [1] 290798 0
HREC/14/SVHM/15
Ethics committee name [2] 292856 0
The University of Western Australia Human Research Ethics Committee (EC00272)
Ethics committee address [2] 292856 0
Ethics committee country [2] 292856 0
Australia
Date submitted for ethics approval [2] 292856 0
23/06/2014
Approval date [2] 292856 0
15/07/2014
Ethics approval number [2] 292856 0
RA/4/1/6939
Ethics committee name [3] 292857 0
The Royal Perth Hospital Human Research Ethics Committee (EC00270)
Ethics committee address [3] 292857 0
Ethics committee country [3] 292857 0
Australia
Date submitted for ethics approval [3] 292857 0
22/09/2014
Approval date [3] 292857 0
20/11/2014
Ethics approval number [3] 292857 0
REG 14-093
Ethics committee name [4] 292858 0
The Tasmanian Health and Medical Human Research Ethics Committee (EC00337)
Ethics committee address [4] 292858 0
Ethics committee country [4] 292858 0
Australia
Date submitted for ethics approval [4] 292858 0
30/10/2014
Approval date [4] 292858 0
11/12/2014
Ethics approval number [4] 292858 0
H0014550

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes
Attachments [1] 1667 1667 0 0
/AnzctrAttachments/366065-BMJ Open-2016-Calderone-6e011028doi10.1136.pdf (Publication)

Contacts
Principal investigator
Name 47318 0
Dr Mandana Nikpour
Address 47318 0
Department of Rheumatology
St Vincent's Hospital Melbourne
PO Box 2900
Fitzroy VIC 3065
Country 47318 0
Australia
Phone 47318 0
+61 3 9231 2211
Fax 47318 0
+61 3 9231 3841
Email 47318 0
[email protected]
Contact person for public queries
Name 47319 0
Mandana Nikpour
Address 47319 0
Department of Rheumatology
St Vincent's Hospital Melbourne
PO Box 2900
Fitzroy VIC 3065
Country 47319 0
Australia
Phone 47319 0
+61 3 9231 2211
Fax 47319 0
+61 3 9231 3841
Email 47319 0
[email protected]
Contact person for scientific queries
Name 47320 0
Mandana Nikpour
Address 47320 0
Department of Rheumatology
St Vincent's Hospital Melbourne
PO Box 2900
Fitzroy VIC 3065
Country 47320 0
Australia
Phone 47320 0
+61 3 9231 2211
Fax 47320 0
+61 3 9231 3841
Email 47320 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
SourceTitleYear of PublicationDOI
EmbaseThe multifaceted problem of pulmonary arterial hypertension in systemic sclerosis.2021https://dx.doi.org/10.1016/S2665-9913%2820%2930356-8
N.B. These documents automatically identified may not have been verified by the study sponsor.