Predictors For Acute And Chronic Pain In Patients With Severe Haemophilia In The PROBE Cohort

Noone D, Chai-Adisaksopha C, Curtis R, Frick N, Nichol M, O’Mahony B, Page D, Pastarnak A, Stonebraker J, Iorio A, Skinner M. Predictors For Acute And Chronic Pain In Patients With Severe Haemophilia In The PROBE Cohort. Poster Presentations #P080. Haemophilia. 2019;25(S1):35-188. https://doi.org/10.1111/hae.13666

Introduction

For people with severe haemophilia, acute and chronic pain is often part of their daily reality. We looked at the extent to which this pain was influenced by annual bleed rate, presence of target joints or joints with reduced range of motion.

Methods

A binary regression analysis was performed to measure the association of acute and chronic pain with selected predictors from the PROBE Phase 2 data. The dependent variable (outcome) was the likelihood of reporting chronic and acute pain. The 5 predictor variables includedin the model were: age, reported annual bleeding rate (ABR), current treatment, presence of a target joint and range of motion (ROM) in a joint.

Results

There were 1287 respondents from 21 countries in total, 658 of whom had severe haemophilia and information for the predictor variables. For acute pain, the univariate logistic regression analysis showed a significant association for ABR (all bleeds) with patients reporting 2-3 bleeds/year being 2.9 times more likely to report acute pain compared to those with 0-1 bleeds/year, and those reporting more than 15 bleeds/year being 10.3 times more likely. Those reporting the presence of a target joint were 2.0 times more likely to report acute pain than thosewithout a target joint. In the full model (all 5 predictors) the impact of ABR is reduced but remains significant. Overall, the full model only predicts 13% of the variation in those who report acute pain. For chronic pain models, the univariate model predicts that those with 2-3 bleeds/year and >15 bleeds/year are 2.2 and 5.5 times more likely to report chronic pain compared to those with 0-1 bleeds/year, explaining 14% of the variance in chronic pain. In the full model however, the most responsible predictor was the presence of a joint with reduced ROM, withthose reporting a limitation being 5 times more likely to report chronic pain than those with full range of motion, which explains 23% of the variance.

Discussion/Conclusion

Our predictors were found to correlate with acute and chronic pain. While acute pain is primarily driven

by the frequency of bleeding and the presence of a target joint, chronic pain is primarily driven by the presence of a joint with reduced range of motion. Therefore, it would be worth exploring whether treatment regimens targeted to reduce annual bleeding rates or those aimed at improving the range of motion would be more effective in reducing chronic pain.

Disclosure of Interest

D. Noone Grant/Research support from: Baxalta, now part of Shire; Bayer; Bioverativ, a Sanofi Company; CSLBehring; Novo Nordisk, Roche and Sobi and the collaboration of the US National Hemophilia Foundation, Chai-Adisaksopha: None Declared, R. Curtis: None Declared, N. Frick: None Declared, M. Nichol: None Declared, B. O’Mahony: None Declared, D. Page: None Declared, A. Pastarnak: None Declared, J. Stonebraker: None Declared, A. Iorio: None Declared, M. Skinner: None Declared

View Poster: Predictors For Acute And Chronic Pain

Impact of Acute and Chronic Pain on the EQ-5D: Insights From The PROBE Study

Noone D, Chai-Adisaksopha C, Curtis R, Frick N, Nichol M, O’Mahony B, Page D, Pastarnak A, Stonebraker J, Iorio A, Skinner M. Impact of Acute and Chronic Pain on the EQ-5D: Insights From The PROBE Study. Poster Presentations #P079. Haemophilia. 2019;25(S1):35-188. https://doi.org/10.1111/hae.13666

Background

Acute and chronic pain as well as the potential access to medications, including haemophilia specific products, significantly impact the quality of life of people with haemophilia (PWH). Generic questionnaires such as the EQ-5D are used to measure the impact of the condition on life experience. EQ-5D in particular is designed to record the individual experience on the day of completion. There is little information on how the response to the pain domain in EQ-5D is driven by acute or chronic pain. The Patient Reported Outcomes, Burdens and Experiences (PROBE) is a questionnaire developed by patients to measure what matters to them in a way that allows comparison with people without bleeding disorders.

Aim and methods

We hypothesized that joint analysis of EQ-5D and PROBE measures would allow deeper understanding of the impact of acute and chronic pain on the respective scores. Descriptive and correlation analysis were performed.

Results

Of 1287 respondents, 686 have severe haemophilia and were examined in this article. We identified 4 subgroups based on responses to PROBE questions asking about acute and chronic pain: no pain (NP, 12.46%), acute pain (AP, 16.13%), chronic pain (CP, 16.23%) and both chronic and acute pain (A/CP, 55.13%). The mean (SD) ages for NP, AP, CP and A/CP were 27.5 (18.3), 24.8 (15.0), 39.2 (15.57) and 37.6 (16.0), respectively. There was a weak correlation (r =0.21, Pearson) between chronic and acute pain.

The mean (SD) EQ-5D utility values for NP, AP, CP and A/CP were 0.91 (0.12), 0.82 (0.21), 0.75 (0.17) and 0.65 (0.28), respectively. Standard t-tests indicated that all groups were statistically different from each other. A similar trend was seen in VAS score.

Conclusion

Acute pain has a significant impact on the quality of life of PWH.  This is further exacerbated by the presence of chronic pain and the combination of both leads to the greatest decrease in quality of life.   The EQ-5D does discern a difference between both types of pain. However, if chronic pain only is present at the time the EQ-5D is administered, the result may mask the full extent of the impact on the utility value unless the context and timing of using these generic tools is understood. It may lead to a misrepresentation of the true nature of pain within the severe haemophilia population.

View Poster: Impact of Acute and Chronic pain on the EQ-5D

Validation of the Patient Reported Outcomes Burdens and Experiences (PROBE) Study Questionnaire

Skinner M, Chai‐Adisaksopha C, O’Mahony B, Noone D, Curtis R, Frick N, Nichol M, Page D, Stonebraker J, Iorio A. Patient Reported Outcomes Burdens and Experiences Study Group. Validation of the Patient Reported Outcomes Burdens and Experiences (PROBE) Study Questionnaire. Abstract PB1412. Res Pract Thromb Haemost. 2019;3(S1):1-891. https://doi.org/10.1002/rth2.12229

Background

A substantial need exists to improve capacity to collect and interpret relevant patient-reported outcomes (PRO) data to support patient-centered research and optimal care in people with hemophilia (PWH).

Aims

Implement a structured data collection of PRO across countries to build a robust evidence base for comparative effectiveness research, evidence-based decision making, and advocacy. Three intermediate objectives were identified:

  • develop a patient-led research network;
  • develop a standardized questionnaire to gather PRO; and
  • perform a feasibility study of implementing the PROBE questionnaire.

Additional aims were to explore the measurement properties of the PROBE questionnaire and demonstrate PROBEis valid to implement for assessing health status among PWH and participants without bleeding disorders acrossregions.

Methods

In data collection from April 2015 to February 2017, 2,101 surveys were collected through all studyphases; 1,541 met study criteria for analysis. Clinical Trial registration: NCT02439710.

Results

Outcomes of importance to PWH and metrics to consider for measurement were determined. The PROBEquestionnaire consists of four major sections (demographic data, general health problems, hemophilia-related healthproblems and health-related quality of life). PROBE questionnaire validation studies establish:

  • Face validity, relevance, clarity and completeness
  • Test-retest reliability (reproducibility)
  • A core analytic framework (psychometric properties)
  • Cross-cultural validation

Conclusions

The PROBE questionnaire is a valid and reliable tool for assessing health status among PWH and participants without bleeding disorders across regions. PROBE assesses patient-important PROs with ademonstrated short completion time. PROBE proved the feasibility to engage diverse patient communities instructured generation of real-world outcome data. The web‐based questionnaire and the paper‐based version maybe used interchangeably. The known group property of PROBE will allow its use in future clinical trials, longitudinalstudies, health technology assessment studies, routine clinical care or registries. Additional studies are planned totest responsiveness and sensitivity to change.

View Poster (English): Validation of PROBE’s Questionnaire

View Poster (Spanish): Validation of PROBE’s Questionnaire

Patient Reported Outcome Data on Switch from Standard to Extended Half Life in Irish Adults with Haemophilia

O’Mahony B, Pastarnak A, Noone A, Skinner M. Patient Reported Outcome Data on Switch from Standard to Extended Half Life in Irish Adults with Haemophilia. Abstract OC 42.4. Res Pract Thromb Haemost. 2019;3(S1):1-228. https://doi.org/10.1002/rth2.12227

Background

From 2017 to the end of 2018, all people with Haemophilia B and the majority with Haemophilia A (PwH) in Ireland were switched to extended half-life FIX (rFIXFc) or FVIII (rFVIIIFc) concentrates.

Objectives

The Irish Haemophilia Society surveyed measurable impact on their health-related quality of life.

Methods

Utilising the Patient Reported Outcomes, Burdens and Experiences (PROBE) survey, the Society surveyed members of the organisation with Haemophilia A/B pre-change and a minimum of 10 months post product change.  There were 12 paired responses from people with Haemophilia B and 5 with haemophilia A.

Results

Three patients switched from episodic treatment to regular prophylaxis (2-HB, 1-HA).

Post-switch, there were reductions in PWH reporting the use of mobility aids (67% to 53%), acute pain (78% to 47%), frequency of use of pain medications, activities of daily living (ADL) being affected, reduced range of motion (83% v 65%) and chronic pain in a target joint (patient defined) (67% to 13%).

There was a significant reduction in reported bleeds.  Pre-switch 29% reported having greater than 8 bleeds/year and 41% having 1 or less bleed/year.  Post-switch there we no responses greater than 8 bleeds/year and 59% having 1 or less bleed/year.

Overall, VAS (68 v 73), EQ-5D (0.71 v 0.77) and PROBE (0.72 v 0.78) score improved post-switch, which equates to ~5-6% increase in utility in a year.  All dimensions of the EQ-5D showed improvement with the most significant changes seen in mobility, self-care and pain/discomfort. (Table 1).

Conclusions

From this initial data set, there is a demonstrated benefit to PWH switching to EHL products in reduced bleeding rates as well as in the physical and pain limitations that haemophilia imposes on daily life. Data collection and analysis are ongoing.

View Presentation: Data on switch from standard to extended half life in Irish adults with haemophilia

Health Status of People Living with Non- severe Hemophilia – Insights from the Patient Reported Outcomes, Burdens and Experiences (PROBE) Study

Chai-Adisaksopha C, Skinner MW, Page D, Stonebraker J, Noone D, Curtis R, Frick N, Nichol M, O’Mahony B, Iorio A, and Patient Reported Outcomes Burdens and Experiences Study Group. Health Status of People Living with Non- severe Hemophilia – Insights from the Patient Reported Outcomes, Burdens and Experiences (PROBE) Study. Abstract OC 32.4. Res Pract Thromb Haemost. 2019;3(S1):1-228. https://doi.org/10.1002/rth2/12227

Background

People living with non-severe hemophilia (PwNSH), FVIII/IX 2-40 IU/dL, generally receive factor concentrate episodically. In recent studies, life expectancy of PwNSH is comparable to the non-hemophilia male population. However, their health status has not been systematically investigated.

Aims

To evaluate the health status of PwNSH

Methods

PROBE data for PwNSH and participants without a bleeding disorder (controls) were analyzed. A match-paired analysis, using 1:1 ratio of PwNSH and controls was performed. Health status of the two groups were compared using parametric or non-parametric methods.

Results

366 participants were included in this analysis. Mean age was 44.7 (SD 17.4) years in PwNSH and 45.8 (SD 14.4) in controls. Table 1 demonstrates health status of participants. Acute pain and chronic pain were more commonly reported among PwNSH (72.4% and 68.1%) compared to controls (37.6% and 30.0%), P< 0.001. Pain medications were more commonly used among PwNSH as compared to controls (86.2% vs 68.0%, P< 0.001). Working full-time was more frequent among controls. PwNSH more frequently reported being on long-term sick or disability compared to controls. Mean sick days per year were significantly higher in PwNSH (3.7 days vs 44.9 days, P< 0.001). Self-evaluated health status using the visual analog scale (VAS) shows that PwNSH had a significantly lower VAS utility score compared to controls (72.8 vs 83.7, P< 0.001). Overall health status, which was evaluated by mean PROBE score, indicated that PwNSH had worse health status compared with controls (0.71 vs 0.89, P< 0.001).

Conclusions

PwNSH had more health-related problems, worse work/school life, and lower health-related quality of life when compared to controls. PROBE findings demonstrate non-severe hemophilia is not a benign disease. Traditional clinical outcomes, e.g., annualized bleeding rate or mortality, are less sensitive to detect health status in PwNSH. We encourage investigators and clinicians to evaluate PwNSH using a patient-reported outcome assessment tool.

View Presentation: Health Status of People Living with Non- severe Hemophilia

Development and testing of the online probe survey and the myPROBE app and integration with the Canadian bleeding disorder registry

Germini F, Borg Debono V, Page D, Skinner MW, Zuk V, Kucher A, Sevestre M, Iorio A, on behalf of PROBE investigators. Development and testing of the online probe survey and the myPROBE app and integration with the Canadian bleeding disorder registry. Abstract P097. Haemophilia. 2020;26(S2):27-181. https://doi.org/10.1111/hae.13911

Introduction

Advances to support accessibility and robust data collection are important in a world of rapidly changing technology.

Methods

To assess future development of software infrastructure of the Patient Reported Outcomes Burdens and Experiences(PROBE) project, we conducted a series of semi-structured interviews of relevant stakeholders, including PROBE investigators, people with hemophilia, and representatives of the sponsors. The Health Information Research Unit team at McMaster University andDesign2Code Inc. developed an online survey using Windows.net technologies and a mobile application for iOS and Android usingreact-native, in collaboration with the PROBE investigators. A user group evaluated the final product using the system usability scale (SUS) and an open feedback framework.

Results

The online survey was updated, a myPROBE app for mobile devices and a new application programming interface were developed. The app was tested and modified according to user feedback over multiple cycles. The final version of the app wasreleased in July 2019. Seventeen users aged 23 to 67 years evaluated the final version of the app using the SUS. The median (first, third quartile) SUS score for the app was 85 (68, 88) out of 100. The newly introduced functionalities are: 1) the capability oflongitudinal tracking repeated fillings of the questionnaire at different time points by the same patients (as opposed to anonymous completion); 2) linking of the questionnaire with hemophilia registries, starting with the Canadian Bleeding Disorders Registry (CBDR) as a proof of concept; 3) removing or adding questions as needed; 4) sending notifications to the users (e.g. reminders). A new secure database was built for securely storing personal information separately from the questionnaire data. Seven hundred and twelve users completed the PROBE questionnaire, 165 of whom used their CBDR credentials. The PROBE online survey is currently available in 60+ countries and 75+ languages.

Discussion/Conclusion

The online survey was updated successfully, and the myPROBE app was developed. In the first months after the product’s release, the responses from testers and users have been largely positive. The median SUS compares well with the top 10 most used and popular apps across all categories (78).

Disclosure of Interest

F. Germini Grant/Research support from: The author’s institution received research supportfrom Roche to conduct this project., V. Borg Debono: None Declared, D. Page: None Declared, M. Skinner Grant/Research support from: Research support as the PROBE study principal investigator from Bayer, CSL, Novo Nordisk, Roche, Sanofi, Sobi and Takeda., V. Zuk: None Declared, A. Kucher: None Declared, M. Sevestre: None Declared, A. Iorio Grant/Research support from: Research support as PROBE study investigator from Bayer, CSL,Novo Nordisk, Roche, Sanofi, Sobi and Takeda.

View Poster: Online PROBE survey and the myPROBE app: integration with the Canadian bleeding disorder registry

Association Between Aging and Health Status in Persons Leaving with Hemophilia and Controls Without a Bleeding Disorder – Insights from the PROBE Study

Germini F, O’Callaghan S, Chai-Adisaksopha C, Curtis R, Frick N, Nichol M, Noone D, O’Mahony B, Page D, Stonebraker J, Skinner M, Iorio A, investigators P. Association Between Aging and Health Status in Persons Leaving with Hemophilia and Controls Without a Bleeding Disorder – Insights from the PROBE Study [Presentation]. ASH (2020), https://ash.confex.com/ash/2020/webprogram/Paper136397.html

Background: People with hemophilia (PWH) have a life expectancy disadvantage as compared to the general population but little is known about the impact of aging on health status and health-related quality of life (HRQL).

Aims

Assessing the characteristics of the association between aging, health status and HRQL in PWH and people with no bleeding disorders (PWNoBD).

Methods

A cross-sectional, multinational study was conducted as part of the Patient Reported Outcomes, Burdens and Experiences (PROBE) project. PWH and PWNoBD were asked to complete the PROBE questionnaire. Measures of health status and HRQL were the PROBE score, the EQ-5D-5L utility index, and the EuroQol visual analog scale (EQ-VAS) of global health. The association between these measures and the age of participants was explored using a multivariable model adjusting for sex (all) and disease severity (PWH only) and stratifying by country.

Results

1157 PWH and 690 PWNoBD completed the questionnaire in 33 countries from 2016 to 2019. Study population demographics are reported in Table 1. Eight percent of the PWH and 12% of the PWNoBD were aged ≥65 years. Multivariable analysis results are reported in Table 2. As expected, the EQ-5D utility index and EQ-VAS did not show a variation with aging in PWNoBD, while in PWH they were reduced respectively by 0.031 (95% confidence interval [CI] 0.021-0.041) and 0.030 (95% CI 0.014-0.047) every 10 years. Aging was associated with a mean reduction in the PROBE score of 0.010 (95% CI 0.004 to 0.017) every 10 years in PWNoBD. PWH showed an additional reduction in the PROBE score of 0.015 (95% CI 0.008 to 0.022) every 10 years.

Conclusions

Aging is associated with a steeper decrease in health status and HRQL in PWH than in PWNoBD. PROBE is more sensitive than EQ5D in measuring the association of aging for the specific domains measured in both PWH and PWNoBD.

View Presentation: Association Between Aging and Health Status

Association Between Aging and Health Status in Persons Leaving with Hemophilia and Controls Without a Bleeding Disorder – Insights from the PROBE Study

Germini F, O’Callaghan S, Chai-Adisaksopha C, Curtis R, Frick N, Nichol M, Noone D, O’Mahony B, Page D, Stonebraker J, Skinner M, Iorio A, investigators P. Association Between Aging and Health Status in Persons Leaving with Hemophilia and Controls Without a Bleeding Disorder – Insights from the PROBE Study [abstract]. Res Pract Thromb Haemost. 2020;4(Suppl 1). https://abstracts.isth.org/abstract/association-between-aging-and-health-status-in-persons-leaving-with-hemophilia-and-controls-without-a-bleeding-disorder-insights-from-the-probe-study/. Accessed June 29, 2020.

Background and aim

People with hemophilia (PWH) have a life expectancy disadvantage as compared to the general population but little is known about the impact of ageing on health status and health-related quality of life (HRQL). The aims of this study were to assess the characteristics of the association between ageing, health status and HRQL in PWH and persons without hemophilia (PWOH).

Methods

A cross-sectional, multinational study was conducted as part of the Patient Reported Outcomes, Burdens and Experiences (PROBE) project. PWH and PWOH were included. Participants were asked to complete the PROBE questionnaire, which contains haemophilia-related, general health and HRQL questions. Measures of health status and HRQL were the PROBE score, the EQ-5D-5L utility index, and the EuroQol visual analog scale (EQ VAS) of global health. The association between these measures and the age of participants was explored using a multivariable generalized linear model adjusting for sex (all) and disease severity (PWH only) and stratifying by country.

Results

1264 PWH and 694 PWOH completed the questionnaire in 33 countries from June 2016 to December 2019. Study population demographics are reported in Table 1. Seven percent of the PWH and 12% of PWOH were aged ≥ 65 years. Multivariable analysis results are reported in Table 2. As expected, the EQ-5D utility index and EQ VAS did not show a variation with ageing in PWOH, while in PWH they were reduced respectively by 0.021 (95%CI 0.015 to 0.028) and 0.033 (95 CI 0.018 to 0.049) every 10 years. Aging was associated with a mean reduction in the PROBE score of 0.01 (95% confidence interval [CI] 0.003 to 0.016) every 10 years in PWOH. PWH showed an additional reduction in the PROBE score of 0.02 (95% CI 0.013 to 0.027) every 10 years.

Conclusions

Ageing is associated with a steeper decrease in health status and HRQL in PWH than in persons without bleeding disorders. PROBE is more sensitive than EQ5D in measuring the association of aging for the specific domains measured in both PWH and PWOH.

View Poster: Association Between Aging and Health Status

 

 

 

3 apps in 1: MyCBDR, myWAPPS and myPROBE

Page D. 3 apps in 1: MyCBDR, myWAPPS and myPROBE. MTD-MP-025 (377).  Haemophilia. 2020;26(Suppl. 4):3-140. https://doi.org/10.1111/hae.13941

Introduction and Objective

MyCBDR is the patient/caregiver bleed and infusion reporting app connected to the Canadian Bleeding Disorder Registry. myWAPPS is an app that enables patients to see their personalized predicted plasma factor levels in real-time. These two apps were connected in July 2019 such that an infusion reported in MyCBDR instantly updates factor levels in myWAPPS. myPROBE is an app that allows people with hemophilia to complete the PROBE survey on-line and, through anonymous registration, be followed longitudinally. It, too, was linked in July 2019 such that the MyCBDR login can be used and MyCBDR users can be followed over time, receive yearly reminders to complete the PROBE survey and receive reports on changes to their PROBE score. The objective of this connectivity is to make data collection more user-friendly, useful and attractive.

Materials and Methods

The Health Information Research Unit team at McMaster University and Design2Code Inc. developed an online survey using Windows.net technologies and a mobile application for iOS and Android using react-native, in collaboration with the PROBE investigators. A user group evaluated the final product using the system usability scale (SUS) and an open feedback framework. In addition, the number of Canadian patients who, after undergoing a previous WAPPS pharmacokinetics study, registered through MyWAPPS was measured.

Results

Seventeen users aged 23 to 67 years evaluated the final version of the PROBE app using the SUS. The median (first, third quartile) SUS score for the app was 85 (68, 88) out of 100. The median SUS compares well with the top 10 most used and popular apps across all categories (78). 165 Canadians with hemophilia used their CBDR credentials to complete the PROBE study. 37 Canadian patients registered for myWAPPS via MyCBDR.

Conclusions

In the first months after the apps were linked, the responses from testers and users have been largely positive. Over time, the inter-connectivity will lead to increased patient/caregiver engagement with their care and improved data collection.

View Poster: 3 apps in 1

Relationship of PROBE Pain Domain and EQ-5D: Insights from the PROBE study

Skinner M, Noone D, Curtis R, Frick N, Germini F, Kucher A, Nichol M, O’Mahony B, Page D, Stonebraker J, Iorio A. P-019 (1035680) Relationship of EQ-5D Pain Domain and Bleeds – Insights from the PROBE Study. (2021), ABSTRACTS. Haemophilia, 27: 3-20. https://doi.org/10.1111/hae.14385

Introduction

Bleeding in people living with haemophilia (PWH) has a significant impact on Health-Related Quality of Life (HRQoL). This impact has been used in terms of disutilities in cost-effectiveness analysis. The aim was to assess the impact on overall HRQoL by severity for a bleed being reported in the last two weeks and assess the level of impact on outcomes.

Methods

Data collected between 2018-2021, was analyzed to determine the relationship of bleeding events being reported within the past two weeks and the PROBE and EQ-5D-5L utility scores. 1168 questionnaires from male PWH A and B ≥ Age 18 (mean[SD] age 41.1[14.5]), were collected in 50 countries. Descriptive analysis and generalised linear models were produced using Stata 13.

Results

The level of pain reported using the EQ-5D-5L pain domain increased across all severities when a PWH reported having a bleed in the past two weeks. Overall, the EQ-5D utility scores were 0.077 (p=0.029), 0.058 (p=0.087) and 0.092 (p< 0.001) higher for mild, moderate and severe patients, respectively, when a bleed was reported in the last two weeks. Using the PROBE score, they were 0.074 (p=0.074), 0.080 (p< 0.001) and 0.089 (p< 0.001) higher. Using a generalised linear model accounting for age, severity and current treatment regimen the disutility associated with a bleed in the last 2 weeks was 0.08 (p< 0.001) for EQ-5D-5L and 0.086 (p< 0.001) for the PROBE score.

Conclusion

Bleeding has a significant impact on PWH HRQoL. A disutility in HRQoL measured by the EQ-5D and PROBE score is evident even two-weeks after a bleeding event. The temporal limitations of the EQ-5D may mask the length of impact of bleeding events unless the context of recent bleeding events is considered. The resulting utility scores may lead to a misrepresentation of the true impact of pain within the severe haemophilia population.

View Poster: PROBE Pain Domain and EQ-5D