Cognitive Behavioral Couple Therapy for Perinatal Distress

The research questions of the study are

• How effective will psychopharmacological treatment, CBCT (with or without Zikr) and combined medicine-CBCT (with or without Zikr) interventions be in reducing symptoms of distress among couples during the perinatal period through a randomized clinical trial?

* Will dyadic coping strategies, social support, domains of quality of life, and well-being be improved in couples at the post-test level compared to the pre-test level by therapeutic intervention through a randomized clinical trial?
* What will be the effect size of post-test intervention?

Procedures and Protocol

The investigator will ask willing participants (screened for high risk) to select one of their preferred treatment modes out of the following

1. Medications (antidepressants and/or anxiolytics).
2. Cognitive Behavioural Therapy without Zikr.
3. Cognitive Behavioural Therapy with Zikr.
4. Combination of medications and cognitive behavioral therapy.
5. Combination of medications, cognitive behavioral therapy, and Zikr.

A list of willing participants will be prepared. Each participant will have one in five chances of getting the preferred treatment mode after study is over. There will be two groups (experimental and control). To put people into one of the two groups, the investigator will select by randomization via online calculator random number generation.

Participants will not know to which group they actually belong. This information will be recorded in the investigator's files, but the research assistant will not look at these files until after the research is finished. This is the best way the investigators have to testing without being influenced by what they think or hope might happen. Thus, the participants and the research assistant will be double blinded in the trial. The investigator and research assistant will then compare which of the two has the best results.

The healthcare professionals (consultant gynecologists and investigator's research assistant) will be looking after the participants very carefully during the study. If there are anything participants are concerned about or that is bothering them about the research they will talk to the researcher, research assistant, gynaecologist or staff.

A placebo or inactive medicine looks like real medicine but it is not. It is a dummy or pretend medicine. It has no effect on a person because it has no real medicine in it. The investigator wants to know whether medicine is good, therefore some people will be given the medicine and others will be given the pretend or a dummy medicine. For the research to be good, it is important that participants do not know whether they have been given real medicine or pretend or dummy medicine. This is one of the best ways the investigator have for knowing what the medicine that are being tested really does. But the participants given a placebo or no intervention will be informed at the end of the study and will be given treatment with medication as they are wait-list control. Moreover, the participants in the intervention group will receive their preferred treatment after the completion of the study.

Participants will receive psychopharmacological treatment according to the National Institute for Health and Care Excellence (NICE) guidelines.

Description of the Process

During the research, a couple has to make ten visits to attend ten sessions in the hospital.

• In the first visit, rapport will be built and pre-test assessment will be done in the following two approaches

Quantitative Approach

• Indigenously developed Parental Perinatal Distress Scale (PPDS).
* Multidimensional Scale for Perceived Social Support (MSPSS).
* Dyadic Coping Inventory (DCI).
* Flourishing Scale (FS).
* World Health Organization's Quality of Life Brief (WOLQOL-BREF)

Qualitative Approach • In a qualitative approach, the semi-structured interviews will be conducted to explore the present stressors and expectations, and perceptions about the effectivity of treatments for perinatal distress among couples.

Group 1 will be given medications or placebo for two weeks and/or for four to five weeks maximum (as per requirement) by the consultant gynaecologist. They have to visit after two weeks for post-test assessment. After treatment, the medicine will be tapered off to stop the intake. As explained before, neither participant will know whether they have received the medicine or the placebo. But in the end placebo participants will be debriefed and will be continued with real medication.

Group 2, Group 3, Group 4 and Group 5 will continue the following 10 sessions (two sessions, each one hour per week) of CBCT with the investigator.

• In the second session, participants will be psycho-educated for perinatal period distress, couples' physical and mental health and impact on the fetus-infant, the prevalence of depression and anxiety, and the significance of identification. Progressive muscle relaxation exercises will be carried out along with deep breathing. Feedback on the session will be taken.

• In the third session, participants will be psycho-educated on the theoretical model of cognitive-behavioral couple therapy with some historical highlights and empirical standing. A thought log will be given for homework. Feedback for deep breathing and progressive muscle relaxation will be carried out.

• In the fourth, fifth, sixth, seventh, eighth, and ninth session, feedback will be taken on homework and session. Various techniques of Cognitive Behavioural Couple Therapy will be applied based on the nature and contents of identified precipitating, perpetuating, and present stressors. In addition, relevant techniques will be incorporated from other modalities with eclecticism. Tasbeeh in Zikr will be given to group 3 and group 5 who opted for it in the screening process.

• On the tenth visit, feedback on the session and homework will be taken. post-test assessment will be done in the following two approaches Group 6 will be exposed to one of the two conditions. 50% of couples will get a placebo and 50% will receive routine treatment care with no intervention. However, after the completion of the research, intervention groups and waitlist group (control) will be briefed and will be delivered with an intervention mode of treatment of their choice as selected earlier.

Posttest assessment will be carried out by the following instruments Quantitative Approach • Indigenously developed Parental Perinatal Distress Scale (PPDS). • Multidimensional Scale for Perceived Social Support (MSPSS). • Dyadic Coping Inventory (DCI).

• Flourishing Scale (FS).
* World Health Organization's Quality of Life Brief (WOLQOL-BREF) Qualitative Approach
* In a qualitative approach, the semi-structured interview will be conducted to explore the conception about the perinatal distress and perceptions about effectivity of treatments for perinatal distress among couples.

Duration The research takes place from 15th August, 2023 to 30th September, 2023. Screening (for Major Depressive Disorder, Generalized Anxiety Disorder) with PPDS will be carried out on the couples who visit the gynecological ward of the hospital in August. After screening and signed informed consent, it will be necessary for participants to come to the clinic/hospital for 10 days in total, for one hour session each day in end of August and whole month of September (two sessions per week, each for one hour).

The investigator and the research assistant would like to meet with participants twice in the upcoming month after the participant's last session visit for a final check-up in follow-ups.

• Psychopharmacological Intervention (Drug): Escitalopram 5-10 mg in antenatal period; Sertraline 12.5-25 mg in postnatal period) and/or Benzodiazepine (Alprazolam, 0.25-0.50 mg).
• Cognitive Behavioral Couple Therapy (Behavioral): CBCT intervention from a trained psychologist in CBT.
• Combination of Psychopharmacological Intervention and CBCT (Other): Medication will be prescribed by a consultant gynecologist and CBCT (conditions: with or without Zikr) will be provided by a trained psychologist.
• Placebo and No Intervention (Other): Control waitlist group will be provided with either a placebo by a consultant gynaecologist or no intervention by a trained psychologist

Primary outcomes

• The Sum of Scores of Major Depressive Disorder Subscale and Generalized Anxiety Disorder Subscale [After recruitment, screening, randomization, and allocation, Pre-test Assessment on week 1 (Baseline Measures) and post-test assessment on week 10 (Outcome Measures) through the study period completion.]: The Generalized Anxiety Disorder Subscale and Major Depressive Disorder Subscale comprised 8 and 14 items respectively in Parental Perinatal Distress Scale. The response categories range from 0 to 3 scale. The total number of items in both subscales is 22. The summed scores obtained on 22 items range from 0 (minimum) to 66 (maximum). The high total score indicates worse symptoms of perinatal distress in the couples. In the present study, data mean and standard deviation specify absolute value at a pre-test and post-test assessment.
• The Sum of Scores on Multidimensional Scale for Perceived Social Support (MSPSS) [After recruitment, screening, randomization, and allocation, Pre-test Assessment on week 1 (Baseline Measures) and post-test assessment on week 10 (Outcome Measures) through the study period completion.]: The Multidimensional Scale for Perceived Social Support comprised 12 items. There are 1 to 7 scoring categories. The sum of score for 12 items range from 12 (minimum) to 84 (maximum). The high score indicates better social support for perinatal couples. In the present study, data mean and standard deviation specifies absolute values in post-test assessment.
• The Sum of Scores on Dyadic Coping Inventory (DCI) [After recruitment, screening, randomization, and allocation, Pre-test Assessment on week 1 (Baseline Measures) and post-test assessment on week 10 (Outcome Measures) through the study period completion.]: Dyadic Coping Inventory comprised 37 items with 1 to 5 scoring categories. However, items 36 and 37 were not included in the scoring as these were evaluative items. The sum of scores for the remaining 35 items range from 35 (minimum) to 175 (maximum). The high score indicates better-than-average levels of coping skills in perinatal couples. In the present study, data mean and standard deviation specifies absolute values in post-test assessment.
• The Sum of Scores on Flourishing Scale (FS) [After recruitment, screening, randomization, and allocation, Pre-test Assessment on week 1 (Baseline Measures) and post-test assessment on week 10 (Outcome Measures) through the study period completion.]: The Flourishing Scale comprised 8 items with 1 to 7 scoring categories. Sum of scores range from 8 (minimum) to 56 (maximum) for eight items. The high score indicates better well-being in perinatal couples. In the present study, data mean and standard deviation specifies absolute values in pre-test and post-test assessment.
• The Sum of Scores on Each Subscale of World Health Organization Quality of Life (WHOQOL-BREF) [After recruitment, screening, randomization, and allocation, Pre-test Assessment on week 1 (Baseline Measures) and post-test assessment on week 10 (Outcome Measures) through the study period completion.]: World Health Organization Quality of Life Bref (WHOQOL-BREF) comprised 26 items with 1 to 5 scoring categories. Item 1 and item 2 were not included in the scoring domains because these were evaluative items. The remaining 24 items are classified in four subscales (physical, psychological, social, and environmental) of quality of life. Sum of scores for physical aspect (7 items) of life ranged from 7 (minimum) to 35 (maximum); 6(minimum) to 30 (maximum) for psychological subscale (6 items); 3 (minimum) to 20 (maximum) for social subscale(3 items); and 8 (minimum) to 40 (maximum) for environmental subscale (8 items) of life. The high score indicates a better quality of life in that particular subscale domain in perinatal couples. In the present study, data mean and standard deviation specifies absolute values in pre-test and post-test assessment.

Secondary outcomes

• Number of Participants With Treatment-related Adverse Events as Assessed by CTCAE v4.0 [After recruitment, screening, randomization, and allocation, number of participants with treatment-related adverse events as assessed by CTCAE v4.0 on week 11 and week 12 (follow-ups) through the study period (two and half months).]: Side effects of escitalopram and sertraline (5 mg/day, and 12.5 mg/day respectively) classified as Grade 1 level in CTCAE v4.0 as these settle down within two to three weeks of medication. A checklist assessed presence or absence of adverse events among participants in psychopharmacological intervention arm, combined intervention without zikr arm, and combined intervention with zikr arm qualitatively. The overall number of participants analyzed in Secondary Outcome Period Participants (1st Oct to 28 Oct) represent the total number of participants for whom an Outcome Measure was measured and analyzed from the Primary Outcome Period Participants, for each Arm/Group. The data were not collected and the outcome cannot be reported for arms without psychopharmacological intervention including "0" participants analyzed because medication was not administered.
• Changes in Blood Concentration (Either ng/ml or mg/L) Levels for Escitalopram and Sertraline [After recruitment, screening, randomization, and allocation, changes in blood concentration levels for Escitalopram and Sertraline as assessed on week 12 (follow-up) through the study period (two and half months).]: Gynaecologist prescribed 5 mg/day escitalopram antenatally or 12.5 mg/day sertraline postnatally. Assessment of blood concentration level via High Performance Liquid Chromatography was conditioned on consent of the participants. The overall number of participants analyzed in Secondary Outcome Period Participants (1st Oct to 28 Oct) represent the total number of participants from the Primary Outcome Period, for each Arm/Group. The data were not collected and the outcome cannot be reported for arms without psychopharmacological intervention including "0" participants. The participants withdrew from HPLC to avoid expansive biomedical tests, adhering to Pakistani cultural norm. The toxicity levels is not reported in the blood of the couples because 5 mg/day escitalopram (Eichentopf et al; Bellantuono et al) or 12.5 mg/day sertraline (Almurjan et al ; Heinonen et al) and is considered safe dose range with no sign of toxicity in blood concentration levels and no presence of adverse events.

Sex: All, ages: 19 Years to 45 Years, accepts healthy volunteers

Inclusion Criteria:

* The fourth month of pregnancy till the seventh month of the antenatal period.
* One week after delivery/birth till one year of a child in the postnatal period.
* Screened by PPDS as high-risk couples (for the level of severe symptomology) for Major Depressive Disorder (cut-off score 29 to 42) and/or Generalized Anxiety Disorder (cut-off score 17 to 24), and their Comorbidity.
* Dose requirements in any one of the antidepressant and/or anxiolytic, such as escitalopram (5-10 mg), sertraline (12.5-25 mg), and/or alprazolam (0.25-0.50 mg) per day.
* Wives accompanied by their husbands.
* Willingness to participate as a couple in the study.
* No physical disorder is present and/or no medication use.
* No psychiatric disorder history or presence
* No psychotropic medication use (presence or history)
* No disability is present.

Exclusion Criteria:

* Unwilling couples to participate in the study.
* Wife and/or couple is in an emergency.
* Wife and/or couple has unstable mental health.
* Wife accompanied by close relatives other than a spouse.
* Wife in the first week of delivery.
* Dose requirements in any one of the antidepressant and/or anxiolytic, such as escitalopram (above10 mg), sertraline (above 25 mg), and/or alprazolam (above 0.50 mg) per day.
* Couples screened with depressive disorder and/or anxiety disorder having psychotic features.
* Couples screened with depressive disorder and/or anxiety disorder having suicidal ideation.
* Couples screened with depressive disorder and/or anxiety disorder having mania/hypomanic features.
* Couples having diabetes.
* Couples having cardiovascular disorders.
* Presence or history of any physical or psychiatric disorder and/or use of medications
* Any intellectual, visual, or hearing disability present in either spouse of a couple.

Participant flow

Outcome results

• The Sum of Scores of Major Depressive Disorder Subscale and Generalized Anxiety Disorder Subscale (Primary), Mean, score on a scale: Psychopharmacological Intervention 18.14 +/- 2.03; CBCT Without Zikr Intervention 17.31 +/- 2.33; CBCT With Zikr Intervention 15.62 +/- 2.47; Combined Intervention Without Zikr 8.62 +/- 1.50; Combined Intervention With Zikr 9.50 +/- 1.35; Placebo Comparator 53.33 +/- 2.87; No Intervention 60.12 +/- 4.12 (p 0.000)
• The Sum of Scores on Multidimensional Scale for Perceived Social Support (MSPSS) (Primary), Mean, score on a scale: Psychopharmacological Intervention 22.14 +/- 1.40; CBCT Without Zikr Intervention 38.31 +/- 4.40; CBCT With Zikr Intervention 47.00 +/- 2.00; Combined Intervention Without Zikr 79.00 +/- 3.20; Combined Intervention With Zikr 80.50 +/- 2.63; Placebo Comparator 18.66 +/- 3.32; No Intervention 18.62 +/- 1.59 (p 0.000)
• The Sum of Scores on Dyadic Coping Inventory (DCI) (Primary), Mean, score on a scale: Psychopharmacological Intervention 105.42 +/- 2.97; CBCT Without Zikr Intervention 153.25 +/- 1.77; CBCT With Zikr Intervention 155.93 +/- 3.83; Combined Intervention Without Zikr 161.37 +/- 3.24; Combined Intervention With Zikr 162.40 +/- 4.90; Placebo Comparator 41.16 +/- 1.16; No Intervention 40.25 +/- 1.48 (p 0.00)
• The Sum of Scores on Flourishing Scale (FS) (Primary), Mean, score on a scale: Psychopharmacological Intervention 19.78 +/- 3.40; CBCT Without Zikr Intervention 38.56 +/- 1.89; CBCT With Zikr Intervention 38.31 +/- 2.33; Combined Intervention Without Zikr 52.37 +/- 2.97; Combined Intervention With Zikr 50.80 +/- 2.57; Placebo Comparator 9.83 +/- 1.60; No Intervention 9.50 +/- 1.51 (p 0.000)
• The Sum of Scores on Each Subscale of World Health Organization Quality of Life (WHOQOL-BREF) (Primary), Mean, score on a scale: Psychopharmacological Intervention 29.07 +/- 2.12; CBCT Without Zikr Intervention 29.12 +/- 2.02; CBCT With Zikr Intervention 30.06 +/- 3.02; Combined Intervention Without Zikr 29.50 +/- 2.07; Combined Intervention With Zikr 30.20 +/- 1.93; Placebo Comparator 10.00 +/- 0.89; No Intervention 10.50 +/- 1.41 (p 0.000)
• Number of Participants With Treatment-related Adverse Events as Assessed by CTCAE v4.0 (Secondary), Count of participants, Participants: Psychopharmacological Intervention 2; CBCT Without Zikr Intervention 0; CBCT With Zikr Intervention 0; Combined Intervention Without Zikr 1; Combined Intervention With Zikr 1; Placebo Comparator 0; No Intervention 0
• Changes in Blood Concentration (Either ng/ml or mg/L) Levels for Escitalopram and Sertraline (Secondary)

Adverse events

Time frame: Adverse event data was assessed on week 11 and week 12 (follow-ups) through the study period (2 and half months).

Serious adverse events by term

Other adverse events by term

• Langan R, Goodbred AJ. Identification and Management of Peripartum Depression. Am Fam Physician. 2016 May 15;93(10):852-8. PMID 27175720
• Schoretsanitis G, Westin AA, Stingl JC, Deligiannidis KM, Paulzen M, Spigset O. Antidepressant transfer into amniotic fluid, umbilical cord blood & breast milk: A systematic review & combined analysis. Prog Neuropsychopharmacol Biol Psychiatry. 2021 Apr 20;107:110228. doi: 10.1016/j.pnpbp.2020.110228. Epub 2021 Jan 2. PMID 33358964
• Nishimura A, Furugen A, Umazume T, Kitamura S, Soma M, Noshiro K, Takekuma Y, Sugawara M, Iseki K, Kobayashi M. Benzodiazepine Concentrations in the Breast Milk and Plasma of Nursing Mothers: Estimation of Relative Infant Dose. Breastfeed Med. 2021 May;16(5):424-431. doi: 10.1089/bfm.2020.0259. Epub 2021 Jan 15. PMID 33449825
• Saito J, Tachibana Y, Wada YS, Yakuwa N, Kawasaki H, Suzuki T, Sago H, Yamatani A, Murashima A. Transfer of brotizolam, periciazine, and sulpiride in cord blood and breast milk, and alprazolam in breast milk: a case report. J Pharm Health Care Sci. 2022 Apr 1;8(1):10. doi: 10.1186/s40780-022-00241-2. PMID 35361275
• Solmi M, Fornaro M, Ostinelli EG, Zangani C, Croatto G, Monaco F, Krinitski D, Fusar-Poli P, Correll CU. Safety of 80 antidepressants, antipsychotics, anti-attention-deficit/hyperactivity medications and mood stabilizers in children and adolescents with psychiatric disorders: a large scale systematic meta-review of 78 adverse effects. World Psychiatry. 2020 Jun;19(2):214-232. doi: 10.1002/wps.20765. PMID 32394557
• Yazdy MM, Mitchell AA, Louik C, Werler MM. Use of selective serotonin-reuptake inhibitors during pregnancy and the risk of clubfoot. Epidemiology. 2014 Nov;25(6):859-65. doi: 10.1097/EDE.0000000000000157. PMID 25171134
• Wilbraham D, Berg PH, Tsai M, Liffick E, Loo LS, Doty EG, Sellers E. Abuse Potential of Lasmiditan: A Phase 1 Randomized, Placebo- and Alprazolam-Controlled Crossover Study. J Clin Pharmacol. 2020 Apr;60(4):495-504. doi: 10.1002/jcph.1543. Epub 2019 Nov 20. PMID 31745991
• Pinheiro E, Bogen DL, Hoxha D, Ciolino JD, Wisner KL. Sertraline and breastfeeding: review and meta-analysis. Arch Womens Ment Health. 2015 Apr;18(2):139-146. doi: 10.1007/s00737-015-0499-y. Epub 2015 Jan 15. PMID 25589155
• Lee H, Koh JW, Kim YA, Chun KC, Han JY, Hwang JH, Choi JS, Joo SH, Kwon HY. Pregnancy and Neonatal Outcomes After Exposure to Alprazolam in Pregnancy. Front Pharmacol. 2022 Apr 25;13:854562. doi: 10.3389/fphar.2022.854562. eCollection 2022. PMID 35548333
• Petric D, Peitl MV, Peitl V. High doses alprazolam induced amenorrhoea and galactorrhoea. Psychiatr Danub. 2011 Mar;23(1):123-4. PMID 21448116
• Akhtar A, Rahman A, Husain M, Chaudhry IB, Duddu V, Husain N. Multidimensional scale of perceived social support: psychometric properties in a South Asian population. J Obstet Gynaecol Res. 2010 Aug;36(4):845-51. doi: 10.1111/j.1447-0756.2010.01204.x. PMID 20666955
• Bodenmann G. Dyadic coping inventory: Test manual. Bern, Switzerland: Huber. 2008.
• Choudhry FR, Al-Worafi YM, Akram B, Ahmed MA, Anwar Ul Haq M, Khan TM, Rehman IU, Barki N, Munawar K, Kamal A, Kassab YW, Bakrin FS, Golden KJ. Factor Structure of Urdu Version of the Flourishing Scale. Front Psychol. 2018 Sep 19;9:1513. doi: 10.3389/fpsyg.2018.01513. eCollection 2018. PMID 30283370
• Diener E, Wirtz D, Biswas-Diener R, Tov W, Kim-Prieto C, Choi DW, Oishi S. New measures of well-being. Assessing well-being: The collected works of Ed Diener. 2009:247-66.
• Saqib Lodhi F, Raza O, Montazeri A, Nedjat S, Yaseri M, Holakouie-Naieni K. Psychometric properties of the Urdu version of the World Health Organization's quality of life questionnaire (WHOQOL-BREF). Med J Islam Repub Iran. 2017 Dec 25;31:129. doi: 10.14196/mjiri.31.129. eCollection 2017. PMID 29951429
• Shafiq S, Bano Z, Randhawa SS, Khan KH, Muhammad QU, Muhammad A. Effectiveness of adapted cognitive behaviour therapy for dysthymia: An evidence based case study. J Pak Med Assoc. 2022 Mar;72(3):554-556. doi: 10.47391/JPMA.1412. PMID 35320244
• Shujja S, Adil A, Randall AK, Bodenmann G, Malik F. Psychometric properties and validity of Dyadic Coping Inventory-Urdu Version for use in Pakistan. Interpersona: An International Journal on Personal Relationships. 2020 Dec 22;14(2):183-99.
• Development of the World Health Organization WHOQOL-BREF quality of life assessment. The WHOQOL Group. Psychol Med. 1998 May;28(3):551-8. doi: 10.1017/s0033291798006667. PMID 9626712
• Zimet GD, Powell SS, Farley GK, Werkman S, Berkoff KA. Psychometric characteristics of the Multidimensional Scale of Perceived Social Support. J Pers Assess. 1990 Winter;55(3-4):610-7. doi: 10.1080/00223891.1990.9674095. PMID 2280326
• Almurjan A, Macfarlane H, Badhan RKS. The application of precision dosing in the use of sertraline throughout pregnancy for poor and ultrarapid metabolizer CYP 2C19 subjects: A virtual clinical trial pharmacokinetics study. Biopharm Drug Dispos. 2021 Jun;42(6):252-262. doi: 10.1002/bdd.2278. Epub 2021 May 5. PMID 33851424
• Heinonen E, Blennow M, Blomdahl-Wetterholm M, Hovstadius M, Nasiell J, Pohanka A, Gustafsson LL, Wide K. Sertraline concentrations in pregnant women are steady and the drug transfer to their infants is low. Eur J Clin Pharmacol. 2021 Sep;77(9):1323-1331. doi: 10.1007/s00228-021-03122-z. Epub 2021 Mar 22. PMID 33751155
• Eichentopf L, Hiemke C, Conca A, Engelmann J, Gerlach M, Havemann-Reinecke U, Hefner G, Florio V, Kuzin M, Lieb K, Reis M, Riemer TG, Serretti A, Schoretsanitis G, Zernig G, Grunder G, Hart XM. Systematic review and meta-analysis on the therapeutic reference range for escitalopram: Blood concentrations, clinical effects and serotonin transporter occupancy. Front Psychiatry. 2022 Oct 17;13:972141. doi: 10.3389/fpsyt.2022.972141. eCollection 2022. PMID 36325531
• Bellantuono C, Bozzi F, Orsolini L. Safety of escitalopram in pregnancy: a case series. Neuropsychiatr Dis Treat. 2013;9:1333-7. doi: 10.2147/NDT.S45951. Epub 2013 Sep 9. PMID 24043940
• Bellantuono C, Bozzi F, Orsolini L, Catena-Dell'Osso M. The safety of escitalopram during pregnancy and breastfeeding: a comprehensive review. Hum Psychopharmacol. 2012 Nov;27(6):534-9. doi: 10.1002/hup.2265. Epub 2012 Oct 9. PMID 23044635

• Study Protocol (PDF, 2023-08-13)
• Statistical Analysis Plan (PDF, 2023-08-13)
• Informed Consent Form (PDF, 2023-08-13)