Development of Women, Girls, and People Who Have or Had the Potential to Menstruate (WGPPM) questionnaire for PROBE study

Kucher A, Skinner M. W., Clearfield E., Brennan F., Rotellini D., Colle Y., Wilton P. A. Development of Women, Girls, and People Who Have or Had the Potential to Menstruate (WGPPM) questionnaire for PROBE study. (2025), Book of Abstracts. Haemophilia, 31: 21-109. https://doi.org/10.1111/hae.70032

Objective

The Patient Reported Outcomes, Burdens, and Experiences (PROBE) survey was first developed in 2012. PROBE currently collects data from people with hemophilia A or B, including carriers, and people without a bleeding disorder (NoBD) who serve as a control group. To date, there has been limited global comparative patient reported data on health outcomes and quality of life (HRQoL) about WGPPM.

Methods

A targeted PubMed literature review was conducted to identify concepts impacting WGPPM quality-of-life. The study team also provided additional examples of past surveys for review. Novel topics and items were mapped to a conceptual framework. The resulting framework was compared to the PROBE questionnaire and subsequently PROBE was updated to include missing concepts. It is anticipated that this exploratory questionnaire will lead to an expanded PROBE to more comprehensively include WGPPM. The questionnaire was developed in consultation with the World Federation of Hemophilia, Coalition of the Americas, European Haemophilia Consortium and National Bleeding Disorders Foundation who constituted the project working group. The new WGPPM questionnaire will be initiated as an on-line survey.

Results

The group identified von Willebrand Disease (VWD), platelet disorders, rare factor deficiencies, and other rare bleeding disorders for inclusion. New concepts include access to healthcare (including specialties); visits to emergency room; bleeding episodes unique to WGPPM (e.g., menstrual bleeding; gynecological problems), decision-making around having children, and impact on social and leisure life.

Conclusions

To advance management and treatment for this underserved population it is crucial to collect and report comprehensive data on WGPPM health outcomes and quality of life.  The WGPPM PROBE exploratory pilot was launched in early 2025. Through this pilot we anticipate more accurate and comprehensive data will be available to support future advocacy, research, management and treatment.  Insights from the pilot will be applied to future PROBE updates.

Poster: HERE

Gene Therapy in Hemophilia A: the Impact of Valoctocogene Roxaparvovec on Patient Outcomes – Initial Results from Patient Reported Outcomes, Burdens and Experiences (PROBE) from the GENEr8-1 Trial

Skinner M, Chen E, Ibrahim Q, Kucher A, Germini F, Karimi M, Clearfield E , O’Mahony B , Jain M. Gene Therapy in Hemophilia A: the Impact of Valoctocogene Roxaparvovec on Patient Outcomes – Initial Results from Patient Reported Outcomes, Burdens and Experiences (PROBE) from the GENEr8-1 Trial. (Abstract). NHF (2023).

Objective

The Patient Reported Outcomes, Burdens and Experiences (PROBE) questionnaire is included in the phase 3, open-label, single-arm study (GENEr8-1) as a tertiary endpoint. The aim is to assess the effect of a single intravenous administration of valoctocogene roxaparvovec on patient-reported health and life experiences using PROBE.

Methods

134 adult men with FVIII ≤1 IU/dL without history of FVIII inhibitors and AAV5 antibodies previously receiving FVIII prophylaxis were enrolled in the GENEr8-1 trial for hemophilia A. Results from baseline, week 52 and week 104 were summarized. The PROBE questionnaire comprises four sections: demographics, general health problems, hemophilia-specific problems, and health-related quality of life (HRQoL) with the 5-level EQ-5D tool. While further validation to understand the performance of PROBE in this context of use is ongoing, this study summarized the initial PROBE summary score results (based on section 2) utilizing existing scoring algorithms. Change from baseline summary score was assessed with paired t-tests.

Summary

PROBE score was available for 124/134 (93%) at baseline, 129/132 (98%) at week 52, and 129/130 (99%) at week 104. Mean PROBE scores (SDs) were 0.82 (0.13), 0.87 (0.12) and 0.86 (0.13) at the baseline, week 52 and week 104 respectively. Average changes in score of  0.05 [95% CI: (0.03, 0.07), p <0.001] and 0.05 (0.02, 0.07), p<0.001) were observed at weeks 52 and 104. Item-level analyses suggested fewer participants reported pain, limitations in activities of daily living, and target joints at weeks 52 and 104 vs. baseline. Two years after treatment, the percentage of participants working full-time increased by >10% (Table 1). Overall, these results were consistent with EQ-5D results (Table 2).

Conclusions

Valoctocogene roxaparvovec led to measurable changes in HRQoL 2 years after a single administration. Further research is necessary to interpret clinically meaningful change in PROBE scores.

Disclosures

Er Chen: Bio Marin Pharmaceutical Inc.; Federico Germini: Bayer Bio Marin Pharmaceutical Inc., Novo Nordisk, Pfizer, Roche, Takeda; Mohit Jain: Bio Marin Pharmaceutical Inc.; Milad Karimi: Bio Marin Pharmaceutical Inc.;

Brian O’Mahony BioMarin Pharmaceutical Inc.CSL Behring; Mark Skinner: Bayer, Bio Marin Pharmaceutical Inc., Blue Cross Blue Shield, ICERMASACNHFNORD, Novo Nordisk, Pfizer, Roche/Genentech, Spark, Takeda, WFH, USA

Poster: HERE

 

Initial results of the impact of valoctocogene roxaparvovec on pain occurrence and interference: Insights from PROBE

Skinner M, Chen E, Kucher A, Germini F, Karimi M, Clearfield E , O’Mahony B , Jain M. Initial results of the impact of valoctocogene roxaparvovec on pain occurrence and interference: Insights from PROBE. (Abstract). NHF (2023).

Introduction

People with severe haemophilia A (PwSHA) commonly present with intramuscular bleeding and hemarthrosis, leading to acute and chronic pain with an overall reduction in health-related quality of life. Here, we report the occurrence of pain in PwSHA before and 2 years after administration of valoctocogene roxaparvovec, and its interference on daily life.

Methods

The Patient Reported Outcomes, Burdens and Experiences (PROBE) questionnaire was included in the phase 3, open-label, single-arm study (GENEr8-1) as a tertiary endpoint to assess the effect of a single 6 × 1013 vg/kg dose of valoctocogene roxaparvovec on patient-reported health and life experiences. While further validation to understand the performance of PROBE in this context of use is ongoing, this study summarized pain-related outcomes collected within the PROBE questionnaire. This analysis evaluated PROBE completions at baseline and 104 weeks post gene therapy, including any occurrence of acute and chronic pain (recall: 12 months) and during eight activities (walking, stair climbing, nighttime, resting, weight bearing, playing, after falling/trauma, other). Participants also reported pain interference in 11 aspects of life (general activity, mood, walking ability, normal work, attending school, relations with others, sleep, enjoyment of life, playing/participating in sports/exercising, lifting, other). Descriptive statistics including 95% confidence intervals (CI) were presented at baseline and Week 104.

Results

Data were available for 124 participants at baseline and 129 at 104 weeks. Median age was 34 (range 21−73 years). Reporting of acute and chronic pain was reduced post gene therapy (acute pain: 60.5% to 41.9%, chronic pain: 65.3% to 57.0%). At 104 weeks, the aggregate instances of self-reported acute pain occurrence decreased from 151 (15.2%) to 113 (10.9%) across the 8 activities (including ‘Other’) [Table 1]. Chronic pain reduced from 238 (24.0%) to 216 (20.9%) [Table 2]. At 104 weeks, the aggregate instances of self-reported acute pain interference decreased from 294 (21.4%) to 204 (14.4%) across the 11 activities (including ‘Other’) [Table 3]. Chronic pain interference was reduced from 332 (24.3%) to 262 (18.5%) [Table 3 and 4].

Conclusions

Initial analysis of PROBE data demonstrates that gene therapy may be associated with a decrease in self-reported acute and chronic pain occurrence and interference with daily life in the study cohort.  Pain is one of the core outcomes of importance to people with haemophilia. The impact of gene therapy on pain, particularly chronic pain as demonstrated from PROBE, a haemophilia-specific tool, has important implications on treatment decision-making and continued disease management.

Disclosures

Er Chen: Bio Marin Pharmaceutical Inc.; Federico Germini: Bayer Bio Marin Pharmaceutical Inc., Novo Nordisk, Pfizer, Roche, Takeda; Mohit Jain: Bio Marin Pharmaceutical Inc.; Milad Karimi: Bio Marin Pharmaceutical Inc.;

Brian O’Mahony BioMarin Pharmaceutical Inc.CSL Behring; Mark Skinner: Bayer, Bio Marin Pharmaceutical Inc., Blue Cross Blue Shield, ICERMASACNHFNORD, Novo Nordisk, Pfizer, Roche/Genentech, Spark, Takeda, WFH, USA

Poster: HERE

 

Initial results of the impact of valoctocogene roxaparvovec on pain occurrence and interference: Insights from PROBE

Skinner M, Chen E, Kucher A, Germini F, Karimi M, Clearfield E , O’Mahony B , Jain M. Initial results of the impact of valoctocogene roxaparvovec on pain occurrence and interference: Insights from PROBE. (2023), CCS_Book of abstracts. Haemophilia, 29: 3-53. https://doi.org/10.1111/hae.14781

Introduction

People with severe haemophilia A (PwSHA) commonly present with intramuscular bleeding and hemarthrosis, leading to acute and chronic pain with an overall reduction in health-related quality of life. Here, we report the occurrence of pain in PwSHA before and 2 years after administration of valoctocogene roxaparvovec, and its interference on daily life.

Methods

The Patient Reported Outcomes, Burdens and Experiences (PROBE) questionnaire was included in the phase 3, open-label, single-arm study (GENEr8-1) as a tertiary endpoint to assess the effect of a single 6 × 1013 vg/kg dose of valoctocogene roxaparvovec on patient-reported health and life experiences. While further validation to understand the performance of PROBE in this context of use is ongoing, this study summarized pain-related outcomes collected within the PROBE questionnaire. This analysis evaluated PROBE completions at baseline and 104 weeks post gene therapy, including any occurrence of acute and chronic pain (recall: 12 months) and during eight activities (walking, stair climbing, nighttime, resting, weight bearing, playing, after falling/trauma, other). Participants also reported pain interference in 11 aspects of life (general activity, mood, walking ability, normal work, attending school, relations with others, sleep, enjoyment of life, playing/participating in sports/exercising, lifting, other). Descriptive statistics including 95% confidence intervals (CI) were presented at baseline and Week 104.

Results

Data were available for 124 participants at baseline and 129 at 104 weeks. Median age was 34 (range 21−73 years). Reporting of acute and chronic pain was reduced post gene therapy (acute pain: 60.5% to 41.9%, chronic pain: 65.3% to 57.0%). At 104 weeks, the aggregate instances of self-reported acute pain occurrence decreased from 151 (15.2%) to 113 (10.9%) across the 8 activities (including ‘Other’) [Table 1]. Chronic pain reduced from 238 (24.0%) to 216 (20.9%) [Table 2]. At 104 weeks, the aggregate instances of self-reported acute pain interference decreased from 294 (21.4%) to 204 (14.4%) across the 11 activities (including ‘Other’) [Table 3]. Chronic pain interference was reduced from 332 (24.3%) to 262 (18.5%) [Table 3 and 4].

Conclusions

Initial analysis of PROBE data demonstrates that gene therapy may be associated with a decrease in self-reported acute and chronic pain occurrence and interference with daily life in the study cohort.  Pain is one of the core outcomes of importance to people with haemophilia. The impact of gene therapy on pain, particularly chronic pain as demonstrated from PROBE, a haemophilia-specific tool, has important implications on treatment decision-making and continued disease management.

Disclosures

Er Chen: Bio Marin Pharmaceutical Inc.; Federico Germini: Bayer Bio Marin Pharmaceutical Inc., Novo Nordisk, Pfizer, Roche, Takeda; Mohit Jain: Bio Marin Pharmaceutical Inc.; Milad Karimi: Bio Marin Pharmaceutical Inc.;

Brian O’Mahony BioMarin Pharmaceutical Inc.CSL Behring; Mark Skinner: Bayer, Bio Marin Pharmaceutical Inc., Blue Cross Blue Shield, ICERMASACNHFNORD, Novo Nordisk, Pfizer, Roche/Genentech, Spark, Takeda, WFH, USA

Oral Presentation: HERE

 

Test-Retest Reliability of a Mobile Application of the Patient Reported Outcomes Burdens and Experiences (PROBE) Study

Curtis R, Wu J, Iorio A, Frick N, Nichol M, Noone D, O’Mahony B, Page D, Stonebraker J, Kucher A, Clearfield E, Skinner MW, Germini F. Test-retest reliability of a mobile application of the patient reported outcomes burdens and experiences (PROBE) study. Haemophilia. 2024 May;30(3):702-708. doi: 10.1111/hae.14969. Epub 2024 Mar 4. PMID: 38439137.

Introduction

The Patient Reported Outcomes, Burdens, and Experiences (PROBE) questionnaire is a patient-reported outcome tool that assesses quality of life and disease burden in people with haemophilia (PWH).

Aim

To assesses the test-retest reliability of PROBE when completed using the mobile phone application.

Methods

We recruited PWH, including carriers, and individuals with no bleeding disorders who attended haemophilia-related workshops or via social media. Participants completed PROBE three times (twice on the app: T1 and T2, and once on the web, T3). Test-retest reliability was analysed for T1 versus T2 (app to app, time period one) and T2 versus T3 (app to web, time period two).

Results

We enrolled 48 participants (median age = 56 [range 27-78] years). Eighteen participants (37.5%) were PWH and seven (14.6%) were carriers. On general health domain questions, we found almost perfect agreement, except for a question on the frequency of use of pain medication in the last 12 months [Kappa coefficient (κ) .72 and .37 for time period one and two, respectively] and any use of pain medications (κ .75) for time period two. For haemophilia-related questions, we found substantial to perfect agreement, except for the questions on the number of joint bleeds in the previous 6 months for time period one (κ .49) and the number of bleeds in the previous two weeks for time period two (κ .34).

Conclusions

The results demonstrate the reliability of the PROBE app. The app can be used interchangeably with the paper and web platforms for PROBE administration.

Disclosures

This disclaimer relates to PubMed, PubMed Central (PMC), and Bookshelf. These three resources are scientific literature databases offered to the public by the U.S. National Library of Medicine (NLM). NLM is not a publisher, but rather collects, indexes, and archives scientific literature published by other organizations. The presence of any article, book, or document in these databases does not imply an endorsement of, or concurrence with, the contents by NLM, the National Institutes of Health (NIH), or the U.S. Federal Government.

Test-Retest Reliability Analysis of the Patient Reported Outcomes Burdens and Experiences (PROBE) Study

Curtis R, Wu J, Iorio A, Nichol M, Germini F, Kucher A, Skinner M. Test-Retest Reliability Analysis of the Patient Reported Outcomes Burdens and Experiences (PROBE) Study. (2023), POSTER ABSTRACTS (PO077). Haemophilia, 29: 24-202. https://doi.org/10.1111/hae.14715

Objective

To investigate the test-retest reliability of the PROBE questionnaire mobile application (MyPROBE).

Methods

People with hemophilia (PWH) including carriers and individuals without a bleeding disorder who attended hemophilia related workshops were invited to participate in this study. Additional participants were recruited through social media. Participants completed PROBE anonymously 3 times: twice on the MyPROBE app (Time 1 and Time 2, ~24 hours apart) and once on the web portal (Time 3, ~14 days after T1). Test-retest reliability was measured calculating the Cohen’s Kappa coefficient for categorical variables, and the correlation coefficient for continuous variables. 

Results

Forty-eight participants were enrolled with a median age (range) of 56 (27-78) years. Of these, 13 (27.1%) were PWH, 12 (25.0%) were carriers of hemophilia A or B and 23 (47.9%) were individuals without a bleeding disorder. On general health domain questions, Kappa coefficients ranged from 0.72 to 1.00, indicating substantial to almost perfect agreement using Cohen’s Kappa for all items (T1 vs T2). T2 vs T3 values ranged from 0.64 to 0.97 with only the acute pain-related questions scoring less than almost perfect agreement. For hemophilia-related domain questions (T1 vs T2), Kappa coefficients ranged from 0.49 to 1.00. Of these, 5 of 8 items were in almost perfect agreement. Values for T2 vs T3 ranged from 0.34 to 1.00, with the time-based bleeding question showing the only coefficient that scored below substantial agreement. For overall health-related quality of life, EQ-5D-5L index scores had a paired mean difference of -0.01 for T1 to T2 and 0.01 for T2 to T3 indicating a near perfect correlation. The correlation coefficients for these two time points were 0.89 and 0.83 respectively. Reliability of the MyPROBE app showed substantial to almost perfect agreement with the web version (T2 to T3). Correlation coefficient of the EQ-visual analog scale (EQ-VAS) for T1 to T2 was 0.90 (0.83 – 0.94) and 0.71 (0.53 – 0.83) for T2 to T3.

Conclusions

The test-retest exercise showed substantial to almost perfect agreement in a majority of questions for the app vs app, and a high correlation for the web vs app. The results suggest the MyPROBE app is a reliable tool to assess patient reported outcomes for PWH and control populations independently of the platform used for its completion.

View Poster: HERE

User-Centered Development and Testing of the Online Patient-Reported Outcomes, Burdens, and Experiences (PROBE) Survey and the myPROBE App and Integration With the Canadian Bleeding Disorder Registry: Mixed Methods Study

Germini F, Borg Debono V, Page D, Zuk V, Kucher A, Cotoi C, Hobson N, Sevestre M, Skinner MW, Iorio A, PROBE Investigators. User-Centered Development and Testing of the Online Patient-Reported Outcomes, Burdens, and Experiences (PROBE) Survey and the myPROBE App and Integration With the Canadian Bleeding Disorder Registry: Mixed Methods Study. JMIR Hum Factors. 2022;9(1):e30797. https://doi.org/10.2196/30797

Evaluation of the sexual health in people living with hemophilia

Germini, F, Chai-Adisaksopha, C, Pete, D, Curtis, R, Frick, N, Nichol, M, Noone, D, O’Mahony, B, Page, D, Stonebraker, J, Thabane, L, Crowther, M, Skinner, M, Iorio, A.  Evaluation of the sexual health in people living with hemophilia. Haemophilia. 2021;27:993-1001. https://doi.org/10.1111/hae.14410

Exploring regional variations in the cross‐cultural, international implementation of the Patient Reported Outcomes Burdens and Experience (PROBE) study

Chai‐Adisaksopha, C, Skinner, MW, Curtis, R, Frick N, Nichol MB, Noone D, O’Mahony B, Page D, Stonebraker J, Thabane L, Crowther MA, Iorio A. Exploring regional variations in the cross‐cultural, international implementation of the Patient Reported Outcomes Burdens and Experience (PROBE) study. Haemophilia. 2019;25:365–372. https://doi.org/10.1111/hae.13703

Test‐retest properties of the Patient Reported Outcomes, Burdens and Experiences (PROBE) questionnaire and its constituent domains

Chai‐Adisaksopha C, Skinner MW, Curtis R, Frick N, Nichol MB, Noone D, O’Mahony B, Page D, Stonebraker J, Thabane L, Crowther MA, Iorio A. Test‐retest properties of the Patient Reported Outcomes, Burdens and Experiences (PROBE) questionnaire and its constituent domains. Haemophilia. 2019;25:75–83. https://doi.org/10.1111/hae.13649