Development and Validation of a Self-assessment System Based on a Mobile App to Manage Adult Growth Hormone Deficiency

AGHD is widely recognized as a specific clinical entity and recombinant human growth hormone (r-hGH) therapy has become a standard practice since 90s thanks to its beneficial effects on body composition, muscle strength, bone mass, cardiovascular risk and patients' exercise capacity and QoL. All the beneficial effects of r-hGH in AGHD patients have been established mainly on selected populations by both few randomized controlled trials (RCTs) and several clinical trials. Real life studies are also available, but they are mainly based on data collected through multicenter sponsored studies such as the Pharmacia \& Upjohn International Metabolic Database (KIMS) and the Hypopituitary Control and Complications Study International Advisory Board (HYPOCCS). All these observational studies suffer from missing data in the original databases and/or lack adequate control group (i.e. untreated GHD patients). Well-conducted real life studies have the advantage to provide information on long-term effects of therapies, as well as on safety, adherence and persistence to therapy. Accordingly, in clinical practice it is common to find a disparity between hormonal levels and patients' subjective well-being: some individuals with a full-blown AGHD do not report any symptom and turn out reluctant to start a treatment, while others with slight GHD experience a deterioration in their QoL that deeply improves after GH replacement. This is mainly due to the fact that clinical presentation of AGHD is frequently based on nonspecific symptoms. Similarly, individual differences in responsiveness to r-hGH are common findings in the real life. Moreover, when other hormonal deficits coexist and patients have to face with a polytherapy, it can be difficult both for clinicians and patients to relate symptoms to the sole AGHD and to verify benefits after treatment. Finally, there is a lack of tools assessing patients' physical activity, which is an important factor to consider when evaluating energy levels, exercise performance, and well-being. Thus, a gap still remains in the real life setting concerning how to measure the improvements occurring in r-hGH treated patients and how to make patients and clinicians more aware of these changes. Nowadays, considering the shortage of established predictive factors for the overall therapeutic response, the decision to whether or not continue treatment depends often on the ratio of perceived and expected benefits over cost and risks of treatment, as well as on the persistent motivation of the patient. These aspects involve also physician's attitude and patient's propensity to start r-hGH replacement therapy. Vice versa the lack of information useful to predict patients' individual response to treatment poses some clinical troubles about how to select patients who may beneficiate from r-hGH therapy. Considering that r-hGH treatment is a chronic therapy requiring a daily self-injection, long-term compliance is still a considerable problem in this setting and is influenced by all the above mentioned issues. It is estimated that about 20 to 30% of patients discontinue the treatment, permanently or for extended periods, making therefore an objective evaluation of the therapeutic effects difficult. All these aspects are enhanced by the paucity of tools available to improve patients' education and awareness of AGHD.

The widespread use of Smartphone applications and wearable devices presents an opportunity to overcome these difficulties in the AGHD management. Although several apps exist to monitor chronic endocrinological diseases, no specific app has been tested in AGHD till now.

In a prospective, 24 months, open-label, monocentric study, an interactive smartphone app (MAGHD App) will be developed, connected to an Integrated Framework (MAGHD Framework) and tested by automatic software testing procedures before the real validation on patients. Subsequently it will be validated on an estimated number of 100 AGHD patients; this system will allow to combine patients' information and HCPs clinical outcomes in a single virtual platform and to return easily accessible data to both AGHD patients and clinicians.

The MAGHD App and the integrated MAGHD Framework will be provided by DataRiver, the research and technological Partner of the study, which is a Contract Research Organization certified by AIFA (Italian drug agency) and accredited as a Research Innovation Institution by the Emilia Romagna Region. The MAGHD software framework will allow integrating patient's Physical Activity data (PA-D), constantly collected by wearable devices (which will be rented and given to patients in the second part of the study), with patient related outcomes data (ePRO-D) and HCP data (HCP-D):

• PA-D will be obtained through wearable devices and will guarantee the automatic collection of data regarding patients' daily life activities. PA recorded by the wearable devices will include: physical activity type, daily steps number, daily walking distance, daily calories burned, sleep duration, sleep quality.
• ePRO-D will be collected via the MAGHD App, which will periodically generate a short question extrapolated from the items of validated questionnaires: AGHDA questionnaire and QLS-H questionnaire for QoL, the Warwick-Edinburgh Mental Well-Being Scale (WEMWBS) for well-being evaluation, the International Index of Erectile Function Questionnaire (IIEF-15) and the Female Sexual Function Index (FSFI) for sexual function evaluation (in men and women respectively), the International Physical Activity Questionnaire (IPAQ) for physical activity evaluation and the Pittsburgh Sleep Quality Index (PSQI) for sleep quality evaluation. Additional information on sexual function, working environment, hobbies and adherence to r-hGH therapy (the latter only in Group 1) will be collected through a simple series of questions taken from a specific chart.

The App will record the number of the user answers as well as the missing ones and will periodically provide a visual satisfaction analogue scale on the use of MAGHD App usability. Patients will be notified by the MAGHD App to promptly answer the periodic surveys. The daily surveys could expire after a predefined time interval to prevent the participants to complete them retrospectively, reducing the risk for recall bias.

• HCP data will include:
• Data obtained from patient's record chart or by interview: anagraphic data, medical history information, comorbidities.
• Data obtained at baseline and at subsequent visits by physical examination, anthropometric parameters, clinical data and symptoms, r-hGH therapy (weekly dose and duration of therapy in months), if ongoing, other hormone replacement treatments (and relative dosage) in case of multiple pituitary deficits.
• Data obtained at baseline and at subsequent visits by clinical (biochemical and radiological) examinations:
• pituitary hormones serum levels (IGF-1, insulin-like growth factor binding protein 3, adrenocorticotropic hormone, cortisol, 24-hour urinary free cortisol, thyroid-stimulating hormone, free thyroxine, free triiodothyronine, luteinizing hormone, follicle-stimulating hormone, estradiol and progesterone (in females), testosterone and sex hormone-binding globulin (in men), prolactin;
• biochemical values (haemoglobin, haematocrit, erythrocytes, leukocytes, platelets, renal and hepatic function, electrolytes, glycaemia, TC, HDL-C, LDL-C, triglycerides, bone metabolism);
• dual-energy X-ray absorptiometry (DEXA) scan for assessing body composition, bone mineral content and bone mineral density on whole skeleton, at lumbar site and at femoral site.

The hormonal-biochemical data will be collected at each visit, while the DEXA scan will be performed at baseline, at 12 months and at the end of the study.

PA-D, ePRO-D and HCP-D will converge in the MAGHD Framework where they will be integrated, analyzed and used to create graphs and tables visible both to patients (in MAGHD App) and clinicians (by a monitoring dashboard).

Patients will receive periodically a feedback concerning: i) %change of their QoL, well-being, sleep quality, sexual function and ii) changes in daily physical activities. This kind of report will enhance patient's awareness on day-by-day changes related to their clinical condition. In particular frequent feedback on QoL and well-being will provide a more objective evaluation of these parameters, thus minimizing possible interference due to life events occurred close to the day in which the questionnaires are filled. Moreover, a summary of the patient's clinical outcomes will be provided through the MAGHD App in a simple graphical way in order to communicate changes in serum IGF-1 and lipid profile.

The project will be carried out in 24 months. Months 1-6 will focus on: 1) App development, 2) Integrated Framework development, 3) App testing.

Patient enrollment and baseline visits will occur between months 1 and 6, then six-month visits (visit 1, visit 2, visit 3 and visit 4) will occur in the next 2 years. In the first phase (12 months) the recruited patients, after having signed the informed consent, will be followed every six months according to our normal clinical practice without using the App and the wearable device (baseline, visit 1 and visit 2). Then they will be trained to use the MAGHD App prior to enter the second phase (following 12 months), in which they will be evaluated every six months during the use of the App and the wearable device (visit 3 and visit 4).

HCP data will be collected both in phase 1 (usual follow-up without the use of MAGHD App) and phase 2 (during the use of MAGHD App). Anamnestic, clinical and biochemical data will be collected at each visit (baseline, visit 2, visit 3, visit 4), while DEXA scan (radiological data) will be performed only twice (at baseline and at the end of the protocol).

All the other data will be collected differently in the two consecutive phases:

• QoL and well-being data:
• In Phase 1 AGHDA questionnaire, QLS-H questionnaire and WEMWBS will be administered to patients in paper form at baseline, visit 1 and visit 2.
• In Phase 2 MAGHD App will periodically generate a short question extrapolated from the items of the same validated questionnaires.
• Sexual function:
• In Phase 1 IIEF-5 questionnaire (for men) and FSFI questionnaire (for woman) will be administered to patients in paper form at baseline, visit 1 and visit 2.
• In Phase 2 MAGHD App will periodically generate a short question extrapolated from the items of the same validated questionnaires.
• Physical activity and sleep quality:
• In Phase 1 physical activity will be evaluated through the IPAQ questionnaire and sleep quality through the PSQI questionnaire; both will be administered to patients in paper form at baseline, visit 1 and visit 2.
• In Phase 2 MAGHD App will periodically generate a short question extrapolated from the items of the same validated questionnaires; data on physical activity and sleep quality will be also automatically collected through wearable devices.
• Additional information on sexual function, working environment, hobbies and adherence to r-hGH therapy (the latter only in Group 1):
• In Phase 1 these aspects will be evaluated at baseline, visit 1 and visit 2, through a specific chart in paper form.
• In Phase 2 the same questions will be sent through the MAGHD App.